Formulations of (s)-3-(1-(9h-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2h)-one

ABSTRACT

Polymorphs of chemical compounds that modulate kinase activity, including PI3 kinase activity, and compounds, pharmaceutical compositions, and methods of treatment of diseases and conditions associated with kinase activity, including PI3 kinase activity, are described herein. Also provided herein are processes for preparing compounds, polymorphs thereof, and pharmaceutical compositions thereof.

CLAIM OF PRIORITY

This application is a continuation application of U.S. patentapplication Ser. No. 16/734,135, filed Jan. 3, 2020, which is adivisional application of U.S. patent application Ser. No. 15/799,612,filed Oct. 31, 2017, now U.S. Pat. No. 10,550,122, which is acontinuation application of U.S. patent application Ser. No. 15/016,117,filed Feb. 4, 2016, now U.S. Pat. No. 9,840,505, which is a divisionalapplication of U.S. patent application Ser. No. 14/327,499, filed Jul.9, 2014, now U.S. Pat. No. 9,290,497, which is a divisional applicationof U.S. patent application Ser. No. 13/347,423, filed Jan. 10, 2012, nowU.S. Pat. No. 8,809,349, which claims the benefit of U.S. ProvisionalApplication No. 61/431,304, filed on Jan. 10, 2011, and U.S. ProvisionalApplication No. 61/578,655, filed on Dec. 21, 2011, all of which areincorporated herein by reference in their entireties.

BACKGROUND

The activity of cells can be regulated by external signals thatstimulate or inhibit intracellular events. The process by whichstimulatory or inhibitory signals are transmitted into and within a cellto elicit an intracellular response is referred to as signaltransduction. Over the past decades, cascades of signal transductionevents have been elucidated and found to play a central role in avariety of biological responses. Defects in various components of signaltransduction pathways have been found to account for a vast number ofdiseases, including numerous forms of cancer, inflammatory disorders,metabolic disorders, vascular and neuronal diseases (Gaestel et al.Current Medicinal Chemistry (2007) 14:2214-2234).

Kinases represent a class of important signaling molecules. Kinases cangenerally be classified into protein kinases and lipid kinases, andcertain kinases exhibit dual specificities. Protein kinases are enzymesthat phosphorylate other proteins and/or themselves (i.e.,autophosphorylation). Protein kinases can be generally classified intothree major groups based upon their substrate utilization: tyrosinekinases which predominantly phosphorylate substrates on tyrosineresidues (e.g., erb2, PDGF receptor, EGF receptor, VEGF receptor, src,abl). serine/threonine kinases which predominantly phosphorylatesubstrates on serine and/or threonine residues (e.g., mTorC1, mTorC2.ATM, ATR, DNA-PK, Akt), and dual-specificity kinases which phosphorylatesubstrates on tyrosine, serine and/or threonine residues.

Lipid kinases are enzymes that catalyze the phosphorylation of lipids.These enzymes, and the resulting phosphorylated lipids and lipid-derivedbiologically active organic molecules play a role in many differentphysiological processes, including cell proliferation, migration,adhesion, and differentiation. Certain lipid kinases are membraneassociated and they catalyze the phosphorylation of lipids contained inor associated with cell membranes. Examples of such enzymes includephosphoinositide(s) kinases (e.g., PI3-kinases, PI4-Kinases),diacylglycerol kinases, and sphihgosine kinases.

Phosphoinositide 3-kinases (PI3Ks) constitute a unique and conservedfamily of intracellular lipid kinases that phosphorylate the 3′-OH groupon phosphatidylinositols or phosphoinositides. The PI3K family comprises15 kinases with distinct substrate specificities, expression patterns,and modes of regulation. The class I PI3Ks (p110α, p110β, p110δ, andp110γ) are typically activated by tyrosine kinases or G-protein coupledreceptors to generate a lipid product termed PIP₃, which engagesdownstream effectors such as those in the Akt/PDK1 pathway, mTOR, theTec family kinases, and the Rho family GTPases. The class II and IIIPI3Ks play a key role in intracellular trafficking through the synthesisof PI(3)P and PI(3,4)P2.

The PI3K signaling pathway is one of the most highly mutated systems inhuman cancers. PI3K signaling is also a key factor in many otherdiseases in humans. PI3K signaling is involved in many disease statesincluding allergic contact dermatitis, rheumatoid arthritis,osteoarthritis, inflammatory bowel diseases, chronic obstructivepulmonary disorder, psoriasis, multiple sclerosis, asthma, disordersrelated to diabetic complications, and inflammatory complications of thecardiovascular system such as acute coronary syndrome.

Many inhibitors of PI3Ks have been generated. While such compounds areoften initially evaluated for their activity when dissolved in solution,solid state characteristics such as polymorphism play an important role.Polymorphic forms of a drug substance, such as an inhibitor of PI3K, canhave different chemical and physical properties, includingcrystallinity, melting point, chemical reactivity, solubility,dissolution rate, optical and mechanical properties, vapor pressure, anddensity. These properties can have a direct effect on the ability toprocess or manufacture a drug substance and the drug product. Moreover,polymorphism is often a factor under regulatory review of the ‘sameness’of drug products from various manufacturers. For example, polymorphismhas been evaluated in compounds such as warfarin sodium, famotidine, andranitidine. Polymorphism can affect the quality, safety, and/or efficacyof a drug product, such as a kinase inhibitor. Thus, research directedtowards polymorphs of PI3K inhibitors and processes for preparingpolymorphs of PI3K inhibitors represents a significantly useful field ofinvestigation in the development of active pharmaceutical ingredients(APIs).

In addition, PI3K inhibitors have been used to treat various diseasesand disorders in humans (e.g., in clinical trials). For the productionof a drug substance intended for use in humans, current GoodManufacturing Practices (GMP) are applicable. Procedures need to be inplace that can control the levels of impurities and ensure that APIproducts are produced which consistently meet their predeterminedspecifications. Thus, a significant need exists for a process to preparePI3K inhibitors suitable for human use, particularly on a commercialscale, that is, inter alia, safe, scalable, efficient, economicallyviable, and/or having other desirable properties. Among other entitic,disclosed herein are polymorphic forms of PI3K inhibitors which addressthese needs and provide exemplary advantages.

SUMMARY

In one embodiment, provided herein are polymorphic forms of a compoundof Formula (I):

herein referred to as Form A, Form B, Form C, Form D, Form E, Form F,Form G, Form H, Form I, Form J, or an amorphous form of a compound ofFormula (I), or a salt, solvate, or hydrate thereof; or a mixture of twoor more thereof. In one embodiment, the polymorphic form of a compoundof Formula (I) can be a crystalline form, a partially crystalline form,an amorphous form, or a mixture of crystalline form(s) and/or amorphousform(s).

In one embodiment, provided herein is a method of preparing a compoundof Formula (I):

or a pharmaceutically acceptable salt, solvate, or hydrate thereof. Inone embodiment, the method comprises any one, two, three, four, five,six, seven, or eight, or more of the following steps:

wherein:

-   -   X is selected from fluoro, chloro, bromo, iodo,        —O—SO₂-4-methylphenyl, and —O—SO₂-methyl;    -   PG¹ is selected from benzyl, substituted benzyl,        methoxycarbonyl, ethoxycarbonyl, substituted ethoxycarbonyl,        9-fluorenyloxycarbonyl, substituted 9-fluorenyloxycarbonyl,        2,2,2,-trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl,        (2-phenyl-2-trimethylsilyl)ethoxycarbonyl,        2-phenylethoxycarbonyl, 1,1-dimethyl-2,2-dibromoethoxycarbonyl,        1,1-dimethyl-2,2,2-trichloroethoxycarbonyl, t-butoxycarbonyl,        1-adamantyloxycarbonyl, 2-adamantyloxycarbonyl,        triisopropylsiloxycarbonyl, vinyloxycarbonyl,        1-isopropoxycarbonyl, 8-quinolyloxycarbonyl,        2,4-dimethylpent-3-yloxycarbonyl, benzyloxycarbonyl, and        substituted benzyloxycarbonyl;    -   PG² is selected from methylsulfonyl, substituted methylsulfonyl,        benzenesulfonyl, substituted benzenesulfonyl, benzyloxycarbonyl,        substituted benzyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl,        2-trimethylsilylethoxycarbonyl, t-butoxycarbonyl,        1-adamantyloxycarbonyl, 2-adamantyloxycarbonyl, alkyl,        substituted alkyl, t-butyldimethylsilyl, triisopropylsilyl,        allyl, benzyl, substituted benzyl, hydroxymethyl, methoxymethyl,        diethoxymethyl, (2-chloroethoxy)methyl, t-butoxymethyl,        t-butyldimethylsiloxymethyl, pivaloyloxymethyl, benzyloxymethyl,        dimethylaminomethyl, 2-tetrahydropyranyl, substituted        alkoxymethyl and substituted aryloxymethyl; and where        substituents are selected from alkyl, heteroalkyl, alkenyl,        alkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl,        heteroarylalkyl, alkoxy, cycloalkoxy, heterocyclyloxy, aryloxy,        heteroaryloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl,        ester, ether, thio, sulfinyl, sulfonyl, sulfonamido, halo,        cyano, hydroxyl, nitro, phosphate, urea, carbamate, and        carbonate.

In one embodiment, provided herein is a method of preparing a polymorphForm C of a compound of Formula (I):

wherein the method comprises:

-   -   (i) exposing a composition comprising at least one non-Form C        polymorph of a compound of Formula (I), or a salt, solvate, or        hydrate thereof, to a non-anhydrous condition for a period of        time sufficient to convert at least about 50% of the total        amount of non-Form C polymorph(s) into Form C of a compound of        Formula (I); and    -   (ii) recovering said polymorph Form C.

In one embodiment, a non-anhydrous condition includes water, such as, ina form of water vapor and/or liquid water. In one embodiment, anon-anhydrous condition includes a solvent system comprising a non-watersolvent and liquid water. In one embodiment, the non-water solvent is awater-miscible solvent. For example, liquid water can be present in anamount of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%,about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%,about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about90%, about 95%, about 96%, about 97%, about 98%, about 99%, or about100% by volume of the solvent system. In one embodiment, liquid water ispresent in an amount of between about 10% and about 50% by volume of thesolvent system.

In one embodiment, a non-anhydrous condition includes a solvent systemcomprising water (e.g., about 90% v/v) and isopropyl alcohol (e.g.,about 10% v/v). In one embodiment, a non-anhydrous condition includes asolvent system comprising water and ethanol. In one embodiment, anon-anhydrous condition includes a solvent system comprising water and awater-miscible solvent, such as, e.g., C₁-C₄ alcohol, acetone,acetonitrile, among others. In one embodiment, a water-miscible solventis an alcohol, such as, e.g., methanol, ethanol, 1-propanol, 2-propanol,1-butanol, 2-butanol, t-butanol, ethylene glycol, among others. In oneembodiment, the ratio of water and water-miscible solvent in a solventsystem provided herein is about 50:1, about 40:1, about 30:1, about20:1, about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1,about 4:1, about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10,about 1:20, about 1:30, about 1:40, or about 1:50 v/v. In oneembodiment, the ratio of water and water-miscible solvent in a solventsystem provided herein is from about 50:1 to about 1:1, from about 40:1to about 1:1, from about 30:1 to about 1:1, from about 20:1 to about1:1, from about 10:1 to about 1:1, from about 9:1 to about 1:1, fromabout 8:1 to about 1:1, from about 7:1 to about 1:1, from about 6:1 toabout 1:1, from about 5:1 to about 1:1, from about 4:1 to about 1.1,from about 3:1 to about 3:1, from about 2:1 to about 1:2, from about 1:1to about 1:4, from about 1:1 to about 1:5, from about 1:1 to about 1:6,from about 1:1 to about 1:7, from about 1:1 to about 1:8, from about 1:1to about 1:9, from about 1:1 to about 1:10, from about 1:1 to about1:20, from about 1:1 to about 1:30, from about 1:1 to about 1:40, orfrom about 1:1 to about 1:50 v/v.

In one embodiment, a non-Form C polymorph is a solid form of a compoundof Formula (I), or a salt, solvate, or hydrate thereof (e.g., acrystalline form, an amorphous form, or a mixture of crystalline form(s)and/or amorphous form(s)), which is not polymorph Form C of a compoundof Formula (I). In one embodiment, a non-Form C polymorph is Form A,Form B, Form D, Form E, Form F, Form G, Form H, Form 1, Form J. or anamorphous form of a compound of Formula (I), or a salt, solvate, orhydrate thereof, or a mixture of two or more thereof. In one embodiment,a non-Form C polymorph can comprise at least about 50% by weightpolymorph Form A of a compound of Formula (I). In one embodiment, anon-Form C polymorph (e.g., Form A or Form B) can be obtained from acomposition comprising Form C.

In one embodiment, provided herein is a method of preparing polymorphForm C of a compound of Formula (I):

wherein the method comprises:

-   -   (i) combining a compound of Formula (Ia):

wherein

-   -   PG² is a protecting group selected from methylsulfonyl,        substituted methylsulfonyl, benzenesulfonyl, substituted        benzenesulfonyl, benzyloxycarbonyl, substituted        benzyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl,        2-trimethylsilylethoxycarbonyl, t-butoxycarbonyl,        1-adamantyloxycarbonyl, 2-adamantyloxycarbonyl, alkyl,        substituted alkyl, t-butyldimethylsilyl, triisopropylsilyl,        allyl, benzyl, substituted benzyl, hydroxymethyl, methoxymethyl,        diethoxymethyl, (2-chloroethoxy)methyl, t-butoxymethyl,        t-butyldimethylsiloxymethyl, pivaloyloxymethyl, benzyloxymethyl,        dimethylaminomethyl, 2-tetrahydropyranyl, substituted        alkoxymethyl and substituted aryloxymethyl, and where        substituents are selected from alkyl, heteroalkyl, alkenyl,        alkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl,        heteroarylalkyl, alkoxy, cycloalkoxy, heterocyclyloxy, aryloxy,        heteroaryloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl,        ester, ether, thio, sulfinyl, sulfonyl, sulfonamido, halo,        cyano, hydroxyl, nitro, phosphate, urea, carbamate, and        carbonate;    -   with one or more reagents to remove the protecting group PG² to        form the compound of Formula (I); and    -   (ii) recovering polymorph Form C of the compound of Formula (I);    -   wherein at least one of steps (i) and (ii) occurs in a        non-anhydrous condition.

In some embodiments, one or more reagents to remove the protecting groupPG² includes, but is not limited to, acids such as HCl. HBr and TFA;carbonate bases, such as Na₂CO₃ and K₂CO₃; hydroxide bases, such as NaOHand KOH; lithium bases, such as methyl lithium, ethyl lithium, propyllithium, n-butyl lithium, n-pentyl lithium, and n-hexyl lithium;oxidants such as ceric ammonium nitrate; hydrogenation conditions, suchas cyclohexadiene/Pd black, and H₂/Pd on carbon; TBAF, and BF₃.Et₂O. Inone embodiment, anon-anhydrous condition includes water, such as in aform of water vapor and/or liquid water. In one embodiment, anon-anhydrous condition includes a solvent system comprising a non-watersolvent and liquid water, as described herein elsewhere.

In certain embodiments, a polymorph provided herein is polymorph Form Cof a compound of Formula (I). In certain embodiments, provided herein isa solid form of a compound of Formula (I) comprising Form C of acompound of Formula (I). In certain embodiments, provided herein is asolid form of a compound of Formula (I) comprising Form C of a compoundof Formula (I), which is substantially pure. In one embodiment, Form Ccan be characterized by having X-ray powder diffraction (XRPD) peaks atabout 10.4, about 13.3, and about 24.3 degrees 2θ. In certainembodiments, Form C is characterized by having differential scanningcalorimetry (DSC) comprising an endotherm at about 208° C. In otherembodiments, Form C is characterized by having differential scanningcalorimetry (DSC) comprising an endotherm at about 208° C., and exothermat about 222° C., and an endotherm at about 280° C. In certainembodiments, Form C can be characterized by thermogravimetric analysiswhere the % weight loss observed is about 1.7% at about 80° C. and about0.2% at about 190° C.

In one embodiment, provided herein is a method of preparing polymorphForm A of a compound of Formula (I):

wherein the method comprises:

-   -   (i) combining a compound of Formula (la):

wherein

-   -   PG² is a protecting group selected from methylsulfonyl,        substituted methylsulfonyl, benzenesulfonyl, substituted        benzenesulfonyl, benzyloxycarbonyl, substituted        benzyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl.        2-trimethylsilylethoxycarbonyl, t-butoxycarbonyl,        1-adamantyloxycarbonyl, 2-adamantyloxycarbonyl, alkyl,        substituted alkyl, t-butyldimethylsilyl, triisopropylsilyl,        allyl, benzyl, substituted benzyl, hydroxymethyl, methoxymethyl,        diethoxymethyl. (2-chloroethoxy)methyl, t-butoxymethyl,        t-butyldimethylsiloxymethyl, pivaloyloxymethyl, benzyloxymethyl,        dimethylaminomethyl, 2-tetrahydropyranyl, substituted        alkoxymethyl and substituted aryloxymethyl, and    -   where substituents are selected from alkyl, heteroalkyl,        alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl,        heteroaryl, heteroarylalkyl, alkoxy, cycloalkoxy,        heterocyclyloxy, aryloxy, heteroaryloxy, amido, amino, acyl,        acyloxy, alkoxycarbonyl, ester, ether, thio, sulfinyl, sulfonyl,        sulfonamido, halo, cyano, hydroxyl, nitro, phosphate, urea,        carbamate, and carbonate;    -   with one or more reagents to remove the protecting group PG² to        form a compound of Formula (I); and    -   (ii) recovering polymorph Form A of the compound of Formula (I).

In some embodiments, step (ii) can include recrystallization of acompound of Formula (I), or a salt, solvate, or hydrate thereof, from amono-solvent system, or from a multi-solvent system that does notcontain both ethyl acetate and hexane. In certain embodiments, themethod further comprises a step of dissolving a compound of Formula (I),or a salt, solvate, or hydrate thereof, in a mono-solvent system or amulti-solvent system, removing residual solid matter to yield a liquidsolution, cooling said liquid solution at a rate to effectcrystallization of Form A. and recovering Form A from the liquidsolution.

In some embodiments, one or more reagents to remove the protecting groupPG² includes, but is not limited to, acids such as HCl. HBr and TFA;carbonate bases, such as Na₂CO₃ and K₂CO₃; hydroxide bases, such as NaOHand KOH; lithium bases, such as methyl lithium, ethyl lithium, propyllithium, n-butyl lithium, n-pentyl lithium, and n-hexyl lithium;oxidants such as ceric ammonium nitrate; hydrogenation conditions, suchas cyclohexadiene/Pd black, and H₂/Pd on carbon; TBAF, and BF₃.Et₂O.

In one embodiment, provided herein is a composition comprising acompound of Formula (I):

or a pharmaceutically acceptable salt, solvate, or hydrate thereof, andone or more pharmaceutically acceptable excipients.

In one embodiment, the composition comprises polymorph Form C. In oneembodiment, the composition comprises a mixture of polymorph Form C andat least one non-Form C polymorph of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or hydrate thereof. Forexample, in certain embodiments, the composition can comprise polymorphForm C and polymorph Form A. In other embodiments, the composition cancomprise polymorph Form C and polymorph Form B. In other embodiments,the composition can comprise polymorph Form C and polymorph Form D. Inother embodiments, the composition can comprise polymorph Form C andpolymorph Form E. In other embodiments, the composition can comprisepolymorph Form C and polymorph Form F. In other embodiments, thecomposition can comprise polymorph Form C and polymorph Form G. In otherembodiments, the composition can comprise polymorph Form C and polymorphForm H. In other embodiments, the composition can comprise polymorphForm C and polymorph Form I. In other embodiments, the composition cancomprise polymorph Form C and polymorph Form J. In other embodiments,the composition can comprise polymorph Form C and an amorphous form of acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or hydrate thereof. In one embodiment, the ratio of polymorph Form C tothe total amount of non-Form C polymorph(s) is greater than about 1:1,greater than about 2:1, greater than about 3:1, greater than about 4:1,greater than about 5:1, greater than about 6:1, greater than about 7:1,greater than about 8:1, or greater than about 9:1. In one embodiment,the composition comprising Form C is a pharmaceutical composition. Inone embodiment, the composition is at least about 98% by weight of acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or hydrate thereof.

In one embodiment, the composition comprises a mixture of polymorph FormA and at least one non-Form A polymorph of a compound of Formula (I), ora pharmaceutically acceptable salt, solvate, or hydrate thereof. Forexample, in certain embodiments, the composition can comprise polymorphForm A and polymorph Form B. In other embodiments, the composition cancomprise polymorph Form A and polymorph Form C. In other embodiments,the composition can comprise polymorph Form A and polymorph Form D. Inother embodiments, the composition can comprise polymorph Form A andpolymorph Form E. In other embodiments, the composition can comprisepolymorph Form A and polymorph Form F. In other embodiments, thecomposition can comprise polymorph Form A and polymorph Form G. In otherembodiments, the composition can comprise polymorph Form A and polymorphForm H. In other embodiments, the composition can comprise polymorphForm A and polymorph Form 1. In other embodiments, the composition cancomprise polymorph Form A and polymorph Form J. In other embodiments,the composition can comprise polymorph Form A and an amorphous form of acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or hydrate thereof. In one embodiment, the ratio of polymorph Form A tothe total amount of non-Form A polymorph(s) is greater than about 1:1,greater than about 2:1, greater than about 3:1, greater than about 4:1,greater than about 5:1, greater than about 6:1, greater than about 7:1,greater than about 8:1, or greater than about 9:1. In one embodiment,the ratio of polymorph Form A to the total amount of non-Form Apolymorph(s) is less than about 1:1, less than about 2:1, less thanabout 3:1, less than about 4:1, less than about 5:1, less than about6:1, less than about 7:1, less than about 8:1, or less than about 9:1.In one embodiment, the composition comprising Form A is a pharmaceuticalcomposition. In one embodiment, the composition is at least about 98% byweight of a compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, or hydrate thereof.

In one embodiment, the composition provided herein is a solid dosageform comprising a polymorph of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or hydrate thereof and one ormore pharmaceutically acceptable excipients. In one embodiment, thecomposition provided herein is a single unit dosage form comprising apolymorph of a compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, or hydrate thereof. In one embodiment, the compositionprovided herein is a tablet or a capsule. In one embodiment, thecomposition provided herein is a capsule.

In one embodiment, the composition provided herein comprises atherapeutically effective amount of a polymorph of a compound of Formula(I), or a pharmaceutically acceptable salt, solvate, or hydrate thereof.In some embodiments, the therapeutically effective amount is about 0.5,about 1, about 2, about 3, about 4, about 5, about 10, about 15, about20, about 25, about 30, about 35, about 40, about 45, about 50, about55, about 60, about 65, about 70, about 75, about 80, about 85, about90, about 95, about 100, about 110, about 120, about 130, about 140,about 150, about 160, about 170, about 180, about 190, about 200, about210, about 220, about 230, about 240, about 250, about 260, about 270,about 280, about 290, about 300, about 325, about 350, about 375, about400, about 425, about 450, about 475, about 500, about 600, about 700,about 800, about 900, or about 1000 mg, or more. In one embodiment, thecomposition provided herein comprises at least one pharmaceuticallyacceptable carrier or excipient. In some embodiments, the compositionprovided herein comprises one or more pharmaceutically acceptablecarrier(s) or excipient(s), including. e.g., microcrystalline cellulose,crospovidone, and/or magnesium stearate. In one embodiment, thecomposition provided herein is an immediate-release dosage form. In someembodiments, the composition provided herein is a hard gelatin capsule.In some embodiments, the composition provided herein is a soft gelatincapsule. In some embodiments, the composition provided herein comprisesForm C of a compound of Formula (I). In some embodiments, thecomposition provided herein comprises Form A of a compound of Formula(I). In some embodiments, the composition provided herein comprises anamorphous form of a compound of Formula (I). In some embodiments, thecomposition provided herein comprises a mixture of two or morepolymorphs of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or hydrate thereof. e.g., polymorphs A, B, C,D, E, F, G, H, I, and J as described herein.

In other embodiments, the composition provided herein is a suspensioncomprising carboxymethyl cellulose and water. In one embodiment, thecomposition provided herein can further comprise one or more excipients,such as, e.g., polysorbate, polyethyleneglycol, cyclodextrin, dextrose,n-methylpyrrolidone, pH buffers, dilute hydrochloric acid,polyoxyethylene esters of 12-hydroxystearic acid, or a mixture of two ormore thereof. Other excipients that can be used in exemplaryformulations include, but are not limited to, fillers such as lactose,mannitol, starch, sorbitol, sucrose, dicalcium phosphate, andmicrocrystalline cellulose; disintegrants such as croscarmellose sodiumand sodium starch glycolate; glidants such as colloidal silicon dioxide,silicon dioxide, magnesium silicate, and talc; lubricants such as sodiumstearyl fumarate and stearic acid; and surfactants such as sodium laurylsulphate, sodium dodecyl sulphate, Tween® 80, and Lutrol®.

In one embodiment, the composition provided herein is used for thetreatment of a PI3K-associated disorder (e.g., a disease or disorderdescribed herein elsewhere or known in the art). In one embodiment, thecomposition provided herein is used for inhibiting PI3K kinase activity.The efficacy of the compound of Formula (I) in these methods and othersas disclosed herein has been described in, for example, US 2009/0312319.

In one embodiment, provided herein is a method of treating aPI3K-associated disorder (e.g., a disorder or disease described hereinelsewhere or known in the art), wherein the method comprisesadministering a polymorph of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or hydrate thereof, to asubject in need thereof. In one embodiment, provided herein is a methodof treating a PI3K-associated disorder, wherein the method comprisesadministering a polymorph of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or hydrate thereof, to asubject in need thereof. In one embodiment, provided herein is a methodof treating a PI3K-associated disorder, wherein the method comprisesadministering a composition provided herein, to a subject in needthereof. In one embodiment, the method comprises administering apolymorph of a compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, or hydrate thereof, or a composition thereof, to asubject in need thereof, orally, parenterally, or topically. In oneembodiment, the method comprises co-administering one or more additionaltherapeutic agent(s) or treating the subject with one or more additionaltherapy(ies) (e.g., radiation therapy or surgery).

DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an X-ray powder diffraction (XRPD) for Polymorph Form A.

FIG. 2 shows an XRPD for Polymorph Form B.

FIG. 3 shows an XRPD for Polymorph Form C.

FIG. 4 shows an XRPD for Polymorph Form D.

FIG. 5 shows an XRPD for Polymorph Form E.

FIG. 6 shows an XRPD for Polymorph Form F.

FIG. 7 shows an XRPD for Polymorph Form G.

FIG. 8 shows an XRPD for Polymorph Form H.

FIG. 9 shows an XRPD for Polymorph Form I.

FIG. 10 shows an XRPD for Polymorph Form J.

FIG. 11 shows an XRPD for amorphous compound of Formula (I).

FIG. 12 shows a differential scanning calorimetry (DSC) thermogram forPolymorph Form A.

FIG. 13 shows a DSC for Polymorph Form B.

FIG. 14 shows a DSC for Polymorph Form C.

FIG. 15 shows a DSC for Polymorph Form D.

FIG. 16 shows a DSC for Polymorph Form E.

FIG. 17 shows a DSC for Polymorph Form F.

FIG. 18 shows a DSC for Polymorph Form G.

FIG. 19 shows a DSC for Polymorph Form H.

FIG. 20 shows a DSC for Polymorph Form I.

FIG. 21 shows a DSC for Polymorph Form J.

FIG. 22 shows a DSC thermogram and a thermogravimetric analysis (TGA)for Polymorph Form A.

FIG. 23 shows two DSC thermograms for Polymorph Form C.

FIG. 24 shows a DSC and a TGA for Polymorph Form F.

FIG. 25 shows a panel of salts tested for formation of crystallinesolids in various solvents.

FIG. 26 shows a single crystal X-ray structure of Polymorph Form G MTBE(t-butyl methyl ether) solvate of a compound of Formula (I).

FIG. 27 shows an FT-IR spectra of Polymorph Form C.

FIG. 28 shows a ¹H-NMR spectra of Polymorph Form C.

FIG. 29 shows a ¹³C-NMR spectra of Polymorph Form C.

FIG. 30 shows a dynamic vapor sorption (DVS) analysis of Polymorph FormC.

FIG. 31 shows representative dissolution profiles of capsules containingPolymorph Form C.

DETAILED DESCRIPTION

Certain features of the disclosure are set forth with particularity inthe appended claims. An understanding of various features and/oradvantages of the present disclosure can be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments.

While various embodiments of the present disclosure have been shown anddescribed herein, it w % ill be apparent to those skilled in the artthat such embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the present disclosure. It should beunderstood that various alternatives to the embodiments described hereincan be employed in view of the present disclosure.

I. Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart.

As used in the specification and claims, the singular form “a”. “an” and“the” includes plural references unless the context clearly dictatesotherwise.

When ranges are used herein for physical properties, such as molecularweight, or chemical properties, such as chemical formulae, allcombinations and subcombinations of ranges and specific embodimentstherein are intended to be included. The term “about” when referring toa number or a numerical range means that the number or numerical rangereferred to is an approximation within experimental variability (orwithin statistical experimental error), and thus the number or numericalrange can vary from, for example, between 1% and 15%, between 1% and10%, between 1% and 5%, between 0.5% and 5%, and between 0.5% and 1%, ofthe stated number or numerical range. As disclosed herein, everyinstance where a number or numerical range preceded by the term “about”also includes the embodiment of the given number(s). For example. “about3° C.” discloses the embodiment of the temperature being “3° C.”. Theterms “about” and “approximately” are used completely interchangeablethroughout the disclosure. The term “between” includes the endpointnumbers on both limits of the range. For example, the range described by“between 3 and 5” is inclusive of the numbers “3” and “5”.

As used herein, and unless otherwise specified. “agent” or “biologicallyactive agent” or “second active agent” refers to a biological,pharmaceutical, or chemical compound or other moiety. Non-limitingexamples include simple or complex organic or inorganic molecules, apeptide, a protein, an oligonucleotide, an antibody, an antibodyderivative, antibody fragment, a vitamin derivative, a carbohydrate, atoxin, or a chemotherapeutic compound. Various compounds can besynthesized, for example, small molecules and oligomers (e.g.,oligopeptides and oligonucleotides), and synthetic organic compoundsbased on various core structures. In addition, various natural sourcescan provide compounds for screening, such as plant or animal extracts,and the like. A skilled artisan can readily recognize that there is nolimit as to the structural nature of the agents of the presentdisclosure.

As used herein, and unless otherwise specified, the term “agonist”refers to a compound having the ability to initiate or enhance abiological function of a target protein, whether by enhancing orinitiating the activity or expression of the target protein.Accordingly, the term “agonist” is defined in the context of thebiological role of the target protein. While agonists provided hereincan specifically interact with (e.g., bind to) the target, compoundsthat initiate or enhance a biological activity of the target protein byinteracting with other members of the signal transduction pathway ofwhich the target protein is a member are also specifically includedwithin this definition.

As used herein, and unless otherwise specified, the terms “antagonist”and “inhibitor” are used interchangeably, and they refer to a compoundhaving the ability to inhibit a biological function of a target protein,whether by inhibiting the activity or expression of the target protein.Accordingly, the terms “antagonist” and “inhibitors” are defined in thecontext of the biological role of the target protein. While antagonistsprovided herein can specifically interact with (e.g., bind to) thetarget, compounds that inhibit a biological activity of the targetprotein by interacting with other members of the signal transductionpathway of which the target protein is a member are also specificallyincluded within this definition. In one embodiment, a biologicalactivity inhibited by an antagonist is associated with the development,growth, or spread of a tumor, or an undesired immune response. e.g., asmanifested in autoimmune disease.

As used herein, and unless otherwise specified, an “anti-cancer agent”,“anti-tumor agent” or “chemotherapeutic agent” refers to any agentuseful in the treatment of a neoplastic condition. One class ofanti-cancer agents comprises chemotherapeutic agents. As used herein,and unless otherwise specified, “chemotherapy” means the administrationof one or more chemotherapeutic drugs and/or other agents to a cancerpatient by various methods, including intravenous, oral, intramuscular,intraperitoneal, intravesical, subcutaneous, transdermal, buccal, orinhalation or in the form of a suppository.

As used herein, and unless otherwise specified, the term “cellproliferation” refers to a phenomenon by which the cell number haschanged as a result of division. In one embodiment, this term alsoencompasses cell growth by which the cell morphology has changed (e.g.,increased in size) consistent with a proliferative signal.

As used herein, and unless otherwise specified, the tem“co-administration,” “administered in combination with,” and theirgrammatical equivalents, encompasses administration of two or moreagents to an animal either simultaneously or sequentially. In oneembodiment, both agents and/or their metabolites are present in theanimal at the same time. In one embodiment, co-administration includessimultaneous administration in separate compositions, administration atdifferent times in separate compositions, or administration in acomposition in which both agents are present.

As used herein, and unless otherwise specified, the tem “effectiveamount” or “therapeutically effective amount” refers to an amount of acompound described herein that is sufficient to effect an intendedapplication or effect, including, but not limited to, disease treatment,as defined herein. The therapeutically effective amount can varydepending upon the intended application (in vitro or in vivo), or thesubject and disease condition being treated, e.g., the weight and age ofthe subject, the severity of the disease condition, the manner ofadministration, and the like, which can be determined by one of ordinaryskill in the art. The term can also apply to a dose that will induce aparticular response in target cells, e.g., reduction of plateletadhesion and/or cell migration. The specific dose will vary depending onthe particular compounds chosen, the dosing regimen to be followed,whether it is administered in combination with other compounds, timingof administration, the tissue to which it is administered, and thephysical delivery system in which it is carried.

As used herein, and unless otherwise specified, the terms “treatment”,“treating”, “palliating” and “ameliorating” are used interchangeablyherein, and refer to an approach for obtaining beneficial or desiredresults, including, but not limited to, a therapeutic benefit and/or aprophylactic benefit. In one embodiment, therapeutic benefit meanseradication or amelioration of the underlying disorder being treated. Inone embodiment, a therapeutic benefit is achieved with the eradicationor amelioration of one or more of the physiological symptoms associatedwith the underlying disorder, such that an improvement is observed inthe patient, notwithstanding that the patient can still be afflictedwith the underlying disorder. For prophylactic benefit, the compositionscan be administered to a patient at risk of developing a particulardisease, or to a patient reporting one or more of the physiologicalsymptoms of a disease, even though a diagnosis of this disease can orcan not have been made.

As used herein, and unless otherwise specified, a “therapeutic effect”encompasses a therapeutic benefit and/or a prophylactic benefit asdescribed herein. A prophylactic effect includes delaying or eliminatingthe appearance of a disease or condition, delaying or eliminating theonset of symptoms of a disease or condition, slowing, halting, orreversing the progression of a disease or condition, or any combinationthereof.

As used herein, and unless otherwise specified, “signal transduction” isa process during which stimulatory or inhibitory signals are transmittedinto and within a cell to elicit an intracellular response. A modulatorof a signal transduction pathway refers to a compound which modulatesthe activity of one or more cellular proteins mapped to the samespecific signal transduction pathway. A modulator can augment (agonist)or suppress (antagonist) the activity of a signaling molecule.

As used herein, and unless otherwise specified, the term “selectiveinhibition” or “selectively inhibit” as applied to a biologically activeagent refers to the agent's ability to selectively reduce the targetsignaling activity as compared to off-target signaling activity, viadirect or interact interaction with the target.

As used herein, and unless otherwise specified, the term “in vivo”refers to an event that takes place in a subject's body.

As used herein, and unless otherwise specified, the term “in vitro”refers to an event that takes places outside of a subject's body. Forexample, an in vitro assay encompasses any assay run outside of asubject assay. In vitro assays encompass cell-based assays in whichcells alive or dead are employed. In one embodiment, in vitro assaysalso encompass a cell-free assay in which no intact cells are employed.

“Subject” to which administration is contemplated includes, but is notlimited to, humans (i.e., a male or female of any age group, e.g., apediatric subject (e.g., infant, child, adolescent) or adult subject(e.g., young adult, middle-aged adult or senior adult)) and/or otherprimates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, includingcommercially relevant mammals such as cattle, pigs, horses, sheep,goats, cats, and/or dogs; and/or birds, including commercially relevantbirds such as chickens, ducks, geese, quail, and/or turkeys.

As used herein, and unless otherwise specified. “radiation therapy”means exposing a patient, using routine methods and compositions knownto the practitioner, to radiation emitters such as alpha-particleemitting radionuclides (e.g., actinium and thorium radionuclides), lowlinear energy transfer (LET) radiation emitters (e.g., beta emitters),conversion electron emitters (e.g., strontium-89 andsamarium-153-EDTMP), or high-energy radiation, including withoutlimitation, x-rays, gamma rays, and neutrons.

As used herein, the term “combining” refers to bringing one or morechemical entities into association with another one or more chemicalentities. Combining includes the processes of adding one or morecompounds to a solid, liquid or gaseous mixture of one or more compounds(the same or other chemical entities), or a liquid solution ormultiphasic liquid mixture. The act of combining includes the process orprocesses of one or more compounds reacting (e.g., bond formation orcleavage; salt formation, solvate formation, chelation, or othernon-bond altering association) with one or more compounds (the same orother chemical entities). The act of combining can include alteration ofone or more compounds, such as by isomerization (e.g., tautomerization,resolution of one isomer from another, racemization

As used herein, the term “recovering” includes, but is not limited to,the action of obtaining one or more compounds by collection duringand/or after a process step as disclosed herein, and the action ofobtaining one or more compounds by separation of one or mom compoundsfrom one or mom other chemical entities during and/or after a processstep as disclosed herein. The term “collection” refers to any action(s)know % n in the art for this purpose, including, but not limited to,decanting a mother liquor from a solid to obtain one or more compounds,and evaporation of liquid media in a solution or other mixture to afforda solid, oil, or other residue that includes one or more compounds. Thesolid can be crystalline, acrystalline, partially crystalline,amorphous, containing one or more polymorphs, a powder, granular, ofvarying particle sizes, of uniform particle size, among othercharacteristics known in the art. An oil can vary in color andviscosity, and include one or more solid forms as a heterogeneousmixture, among other characteristics known in the art. The term“separation” refers to any action(s) known in the art for this purpose,including, but not limited to, isolating one or more compounds from asolution or mixture using, for example, seeded or seedlesscrystallization or other precipitation techniques (e.g., adding ananti-solvent to a solution to induce compound precipitation; heating asolution, then cooling to induce compound precipitation; scratching thesurface of a solution with an implement to induce compoundprecipitation), and distillation techniques. Recovering one or morecompounds can involve preparation of a salt, solvate, hydrate, chelateor other complexes of the same, then collecting or separating asdescribed above.

As used herein, a “pharmaceutically acceptable form” of a disclosedFormula (I) includes, but is not limited to, pharmaceutically acceptablesalts, hydrates, solvates, chelates, non-covalent complexes, isomers,prodrugs, and isotopically labeled derivatives thereof, and mixturesthereof. Hence, the terms “chemical entity” and “chemical entities” alsoencompass pharmaceutically acceptable salts, hydrates, solvates,chelates, non-covalent complexes, isomers, prodrugs, and isotopicallylabeled derivatives, and mixtures thereof. In some embodiments, apharmaceutically acceptable form of a disclosed Formula (I) includes asalt, a solvate, or a hydrate thereof.

In certain embodiments, the pharmaceutically acceptable form is apharmaceutically acceptable salt. As used herein, the term“pharmaceutically acceptable salt” refers to those salts which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of subjects without undue toxicity, irritation,allergic response and the like, and are commensurate with a reasonablebenefit/risk ratio. Pharmaceutically acceptable salts are well known inthe art. For example. Berge el a, describes pharmaceutically acceptablesalts in detail in J. Pharmaceutical Sciences (1977) 66:1-19.Pharmaceutically acceptable salts of the compounds provided hereininclude those derived from suitable inorganic and organic acids andbases. Inorganic acids from which salts can be derived include, but arenot limited to, hydrochloric acid, hydrobromic acid, sulfuric acid,nitric acid, phosphoric acid, and the like. Organic acids from whichsalts can be derived include, but are not limited to, acetic acid,propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid,malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and thelike. Examples of pharmaceutically acceptable, nontoxic acid additionsalts are salts of an amino group formed with inorganic acids such ashydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid andperchloric acid or with organic acids such as acetic acid, oxalic acid,maleic acid, tartaric acid, citric acid, succinic acid or malonic acidor by using other methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, besylate, benzoate, bisulfate, borate,butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. In some embodiments, organic acids from which salts can bederived include, for example, acetic acid, propionic acid, glycolicacid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinicacid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamicacid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceuticallyacceptable salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄ alkyl)⁴- salts. Inorganicbases from which salts can be derived include, but are not limited to,sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc,copper, manganese, aluminum, and the like. Organic bases from whichsalts can be derived include, but are not limited to, primary,secondary, and tertiary amines, substituted amines, including naturallyoccurring substituted amines, cyclic amines, basic ion exchange resins,and the like, examples include, but are not limited to, isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine, andethanolamine. In some embodiments, the pharmaceutically acceptable baseaddition salt is ammonium, potassium, sodium, calcium, or magnesiumsalts. Representative alkali or alkaline earth metal salts includesodium, lithium, potassium, calcium, magnesium, iron, zinc, copper,manganese, aluminum, and the like. Further pharmaceutically acceptablesalts include, when appropriate, nontoxic ammonium, quatemary ammonium,and amine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and arylsulfonate. Organic bases from which salts can be derived include, forexample, primary, secondary, and tertiary amines, substituted aminesincluding naturally occurring substituted amines, cyclic amines, basicion exchange resins, and the like, such as isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine, andethanolamine. In some embodiments, the pharmaceutically acceptable baseaddition salt is chosen from ammonium, potassium, sodium, calcium, andmagnesium salts. Bis salts (i.e., two counterions) and higher salts(e.g., three or more counterions) are encompassed within the meaning ofpharmaceutically acceptable salts.

In addition, if a compound of the present disclosure is obtained as anacid addition salt, the free base can be obtained by basifying asolution of the acid salt. Conversely, if a product is a free base, anacid addition salt, particularly a pharmaceutically acceptable additionsalt, can be produced by dissolving the free base in a suitable organicsolvent and treating the solution with an acid, in accordance withconventional procedures for preparing acid addition salts from basecompounds. Those skilled in the art will recognize various syntheticmethodologies that can be used to prepare non-toxic pharmaceuticallyacceptable addition salts.

In certain embodiments, the pharmaceutically acceptable form is a“solvate” (e.g., a hydrate). As used herein, the term “solvate” refersto compounds that further include a stoichiometric or non-stoichiometricamount of solvent bound by non-covalent intermolecular forces. Thesolvate can be of a disclosed compound or a pharmaceutically acceptablesalt thereof. Where the solvent is water, the solvate is a “hydrate”.Pharmaceutically acceptable solvates and hydrates are complexes that,for example, can include 1 to about 100, or 1 to about 10, or one toabout 2, 3 or 4, solvent or water molecules. In some embodiments, thehydrate can be a channel hydrate. It will be understood that the term“compound” as used herein encompasses the compound and solvates of thecompound, as well as mixtures thereof.

As used herein, and unless otherwise specified, “prodrug” is meant toindicate a compound that can be converted under physiological conditionsor by solvolysis to a biologically active compound described herein.Thus, the term “prodrug” refers to a precursor of a biologically activecompound that is pharmaceutically acceptable. A prodrug can be inactivewhen administered to a subject, but is converted in vivo to an activecompound, for example, by hydrolysis. In some embodiments, the prodrugcompound often offers advantages of solubility, tissue compatibility ordelayed release in a mammalian organism (see. e.g., Bundgard. H., Designof Prodrugs (1985), pp. 7-9.21-24 (Elsevier. Amsterdam). A discussion ofprodrugs is provided in Higuchi. T., et al., “Pro-drugs as NovelDelivery Systems.” A.C.S. Symposium Series, Vol. 14, and inBioreversible Carriers in Drug Design, ed. Edward B. Roche, AmericanPharmaceutical Association and Pergamon Press, 1987, both of which areincorporated in full by reference herein. The term “prodrug” is alsomeant to include any covalently bonded carriers, which release theactive Formula (I)n vivo when such prodrug is administered to amammalian subject. Prodrugs of an active compound, as described herein,can be prepared by modifying functional groups present in the activeFormula (I)n such a way that the modifications are cleaved, either inroutine manipulation or in vivo, to the parent active compound. Prodrugsinclude compounds wherein a hydroxy, amino or mercapto group is bondedto any group that, when the prodrug of the active Formula (I) isadministered to a mammalian subject, cleaves to form a free hydroxy,free amino or free mercapto group, respectively. Examples of prodrugsinclude, but am not limited to, acetate, formate, and benzoatederivatives of an alcohol; or acetamide, formamide, and benzamidederivatives of an amine functional group in the active compound, and thelike. Other examples of prodrugs include compounds that comprise —NO.—N_(O2), —ONO, or —ON_(O2) moieties. Prodrugs can typically be preparedusing well-known methods, such as those described in Burger's MedicinalChemistry and Drug Discovery. 172-178, 949-982 (Manfred E. Wolff ed.,5th ed., 1995), and Design of Prodrugs (H. Bundgaard ed., Elselvier, NewYork, 1985).

For example, if a disclosed compound or a pharmaceutically acceptableform of the compound contains a carboxylic acid functional group, aprodrug can comprise a pharmaceutically acceptable ester formed by thereplacement of the hydrogen atom of the acid group with a group such as(C₁-C₈)alkyl. (C₂-C₁₂)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl havingfrom 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbonatoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms.N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-methylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl.

Similarly, if a disclosed compound or a pharmaceutically acceptable formof the compound contains an alcohol functional group, a prodrug can beformed by the replacement of the hydrogen atom of the alcohol group witha group such as (C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl(C₁-C₆)alkoxycarbonyloxymethyl.N—(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl.α-amino(C₁-C₄)alkanoyl, arylacyl and α-aminoacyl, orα-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independentlyselected from the naturally occurring L-amino acids. P(O)(OH)₂,—P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting from theremoval of a hydroxyl group of the hemiacetal form of a carbohydrate).

If a disclosed compound or a pharmaceutically acceptable form of theFormula (I)ncorporates an amine functional group, a prodrug can beformed by the replacement of a hydrogen atom in the amine group with agroup such as R-carbonyl. RO-carbonyl, NRR′-carbonyl where R and R′ areeach independently (C₁-C₁₀)alkyl, (C₃-C₇)cycloalkyl, benzyl, a naturalα-aminoacyl or natural α-aminoacyl-natural α-aminoacyl, —C(OH)C(O)OY¹herein Y¹ is H. (C₁-C₆)alkyl or benzyl. —C(OY²)Y³ wherein Y² is (C₁-C₄)alkyl and Y³ is (C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl, amino(C₁-C₄)alkyl ormono-N— or di-N,N—(C₁-C₆)alkylaminoalkyl. —C(Y⁴)Y⁵ wherein Y⁴ is H ormethyl and Y⁵ is mono-N— or di-N,N—(C₁-C₆)alkylamino, morpholino,piperidin-1-yl or pyrrolidin-1-yl.

In certain embodiments, the pharmaceutically acceptable form is anisomer. “Isomers” ae different compounds that have the same molecularformula. “Stereoisomers” are isomers that differ only in the way theatoms are arranged in space. As used herein, the term “isomer” includesany and all geometric isomers and stereoisomers. For example. “isomers”include geometric double bond cis- and trans-isomers, also termed E- andZ-isomers: R- and S-enantiomers; diastereomers, (d)-isomers and(I)-isomers, racemic mixtures thereof: and other mixtures thereof, asfalling within the scope of this disclosure.

Substituents around a carbon-carbon double bond alternatively can bereferred to as “cis” or “trans,” where “cis” represents substituents onthe same side of the double bond and “trans” represents substituents onopposite sides of the double bond. The arrangement of substituentsaround a carbocyclic ring can also be designated as “cis” or “trans.”The term “cis” represents substituents on the same side of the plane ofthe ring, and the term “trans” represents substituents on opposite sidesof the plane of the ring. Mixtures of compounds wherein the substituentsare disposed on both the same and opposite sides of plane of the ringare designated “cis/trans.”

“Enantiomers” are a pair of stereoisomers that are non-superimposablemirror images of each other. A mixture of a pair of enantiomers in anyproportion can be known as a “racemic” mixture. The term “(*)” is usedto designate a racemic mixture where appropriate. “Diastereoisomers” arestereoisomers that have at least two asymmetric atoms, but which are notmirror-images of each other. The absolute stereochemistry is specifiedaccording to the Cahn-Ingold-Prelog R-S system. When a Formula (I)s anenantiomer, the stereochemistry at each chiral carbon can be specifiedby either R or S. Resolved compounds whose absolute configuration isunknown can be designated (+) or (−) depending on the direction (dextro-or levorotatory) which they rotate plane polarized light at thewavelength of the sodium D line. Certain of the compounds describedherein contain one or more asymmetric centers and can thus give rise toenantiomers, diastereomers, and other stereoisomeric forms that can bedefined, in terms of absolute stereochemistry at each asymmetric atom,as (R)- or (S)-. The present chemical entities, pharmaceuticalcompositions and methods are meant to include all such possible isomers,including racemic mixtures, optically substantially pure forms andintermediate mixtures. Optically active (R)- and (S)-isomers can beprepared, for example, using chiral synthons or chiral reagents, orresolved using conventional techniques.

As used herein, and unless otherwise specified, the term“stereomerically pure” means a composition or substance that comprisesone stereoisomer of a compound and is substantially free of otherstereoisomers of that compound. For example, a stereomerically purecomposition of a compound having one chiral center will be substantiallyfree of the opposite enantiomer of the compound. A stereomerically purecomposition of a compound having two chiral centers will besubstantially free of other stereoisomers (e.g., diastereoisomers orenantiomers, or syn or anit isomers, or cis or trans isomers) of thecompound. A typical stereomerically pure compound comprises greater thanabout 80 percent by weight of one stereoisomer of the compound and lessthan about 20 percent by weight of other stereoisomers of the compound,greater than about 90 percent by weight of one stereoisomer of thecompound and less than about 10 percent by weight of the otherstereoisomers of the compound, greater than about 95 percent by weightof one stereoisomer of the compound and less than about 5 percent byweight of the other stereoisomers of the compound, or greater than about97 percent by weight of one stereoisomer of the compound and less thanabout 3 percent by weight of the other stereoisomers of the compound.

As used herein, and unless otherwise specified, the term“enantiomerically pure” means a stereomerically pure composition of acompound having one or more chiral center(s).

As used herein, and unless otherwise specified, the terms “enantiomericexcess” and “diasteromeric excess” are used interchangeably herein. Insome embodiments, compounds with a single stereocenter can be referredto as being present in “enantiomeric excess.” and those with at leasttwo stereocenters can be referred to as being present in “diasteromericexcess.” For example, the term “enantiomeric excess” is well known inthe art and is defined as:

${ee}_{a} = {\left( \frac{{{{conc}.{of}}a} - {{{conc}.{of}}b}}{{{{conc}.{of}}a} + {{{conc}.{of}}b}} \right) \times 100}$

Thus, the term “enantiomeric excess” is related to the term “opticalpurity” in that both are measures of the same phenomenon. The value ofcc will be a number from 0 to 100, zero being racemic and 100 beingenantiomerically pure. A compound which in the past might have beencalled 98% optically pure is now more precisely characterized by 96% cc.A 90% cc reflects the presence of 95% of one enantiomer and 5% of theother(s) in the material in question.

Some compositions described herein contain an enantiomeric excess of atleast about 50%, 75%, 90%, 95%, or 99% of the S enantiomer. In otherwords, the compositions contain an enantiomeric excess of the Senantiomer over the R enantiomer. In other embodiments, somecompositions described herein contain an enantiomeric excess of at leastabout 50%, 75%, 90%, 95%, or 99% of the R enantiomer. In other words,the compositions contain an enantiomeric excess of the R enantiomer overthe S enantiomer.

For instance, an isomer/enantiomer can, in some embodiments, be providedsubstantially free of the corresponding enantiomer, and can also bereferred to as “optically enriched.” “enantiomerically enriched,”“enantiomerically pure” and “non-racemic,” as used interchangeablyherein. These terms refer to compositions in which the percent by weightof one enantiomer is greater than the amount of that one enantiomer in acontrol mixture of the racemic composition (e.g., greater than about 1:1by weight). For example, an enantiomerically enriched preparation of theS enantiomer, means a preparation of the compound having greater thanabout 50% by weight of the S enantiomer relative to the R enantiomer,such as at least about 75% by weight, further such as at least about 80%by weight. In some embodiments, the enrichment can be much greater thanabout 80% by weight, providing a “substantially enantiomericallyenriched,” “substantially enantiomerically pure” or a “substantiallynon-racemic” preparation, which refers to preparations of compositionswhich have at least about 85% by weight of one enantiomer relative toother enantiomer, such as at least about 90% by weight, and further suchas at least 95% by weight. In certain embodiments, the compound providedherein is made up of at least about 90% by weight of one enantiomer. Inother embodiments, the Formula (I)s made up of at least about 95%, 98%,or 99% by weight of one enantiomer.

In some embodiments, the Formula (I) is a racemic mixture of (S)- and(R)-isomers. In other embodiments, provided herein is a mixture ofcompounds wherein individual compounds of the mixture existpredominately in an (S)- or (R)-isomeric configuration. For example, thecompound mixture has an (S)-enantiomeric excess of greater than about55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%,about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about99.5%, or more. In other embodiments, the compound mixture has an(S)-enantiomeric excess of greater than about 55% to about 99.5%,greater than about 60% to about 99.5%, greater than about 65% to about99.5%, greater than about 70% to about 99.5%, greater than about 75% toabout 99.5%, greater than about 80% to about 99.5%, greater than about85% to about 99.5%, greater than about 90% to about 99.5%, greater thanabout 95% to about 99.5%, greater than about 96% to about 99.5%, greaterthan about 97% to about 99.5%, greater than about 98% to greater thanabout 99.5%, greater than about 99% to about 99.5%, or more.

In other embodiments, the compound mixture has an (R)-enantiomericpurity of greater than about 55%, about 60%, about 65%, about 70%, about75%, about 80%, about 85%, about 90%, about 95%, about %%, about 97%,about 98%, about 99%, about 99.5% or more. In some other embodiments,the compound mixture has an (R)-enantiomeric excess of greater thanabout 55% to about 99.5%, greater than about 60% to about 99.5%, greaterthan about 65% to about 99.5%, greater than about 70% to about 99.5%,greater than about 75% to about 99.5%, greater than about 80% to about99.5%, greater than about 85% to about 99.5%, greater than about 90% toabout 99.5%, greater than about 95% to about 99.5%, greater than about96% to about 99.5%, greater than about 97% to about 99.5%, greater thanabout 98% to greater than about 99.5/a greater than about 99% to about99.5% or more.

In other embodiments, the compound mixture contains identical chemicalentitics except for their stereochemical orientations, namely (S)- or(R)-isomers. For example, if a compound disclosed herein has —CH(R)—unit, and R is not hydrogen, then the —CH(R)— is in an (S)- or(R)-stereochemical orientation for each of the identical chemicalentities. In some embodiments, the mixture of identical chemicalentities is a racemic mixture of (S)- and (R)-isomers. In anotherembodiment, the mixture of the identical chemical entities (except fortheir stereochemical orientations), contain predominately (S)-isomers orpredominately (R)-isomers. For example, the (S)-isomers in the mixtureof identical chemical entities are present at about 55%, about 60%,about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or more,relative to the (R)-isomers. In some embodiments, the (S)-isomers in themixture of identical chemical entities are present at an(S)-enantiomeric excess of greater than about 55% to about 99.5%,greater than about 60% to about 99.5%, greater than about 65% to about99.5%, greater than about 70% to about 99.5%, greater than about 75% toabout 99.5%, greater than about 80% to about 99.5%, greater than about85% to about 99.5%, greater than about 90% to about 99.5%, greater thanabout 95% to about 99.5%, greater than about 96% to about 99.5%, greaterthan about 97% to about 99.5%, greater than about 98% to greater thanabout 99.5%, greater than about 99% to about 99.5% or more.

In another embodiment, the (R)-isomers in the mixture of identicalchemical entities (except for their stereochemical orientations), arepresent at about 55%, about 60%, about 65%, about 70%, about 75% a,about 80%, about 85%, about 90′6, about 95%, about 96%, about 97%, about98/a, about 99%, about 99.5%, or more, relative to the (S)-isomers. Insome embodiments, the (R)-isomers in the mixture of identical chemicalentities (except for their stereochemical orientations), are present ata (R)-enantiomeric excess greater than about 55% to about 99.5%, greaterthan about 60% to about 99.5%, greater than about 65% to about 99.5%,greater than about 70% to about 99.5%, greater than about 75% to about99.5%, greater than about 80% to about 99.5%, greater than about 85% toabout 99.5%, greater than about 90% to about 99.5%, greater than about95% to about 99.5%, greater than about 96% to about 99.5%, greater thanabout 97% to about 99.5%, greater than about 98% to greater than about99.5%, greater than about 99% to about 99.5/c, or more.

Enantiomers can be isolated from racemic mixtures by any method known tothose skilled in the art, including chiral high pressure liquidchromatography (HPLC), the formation and crystallization of chiralsalts, or prepared by asymmetric syntheses. See, for example.Enantiomers. Racemates and Resolutions (Jacques. Ed., WileyInterscience, New York, 198l); Wilen et al., Tetrahedron 33:2725 (1977);Stereochemistry of Carbon Compounds (E. L. Elicl, Ed., McGraw-Hill, N Y,1962); and Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Elicl. Ed., Univ. of Notre Dame Press, Notre Dame, Ind. 1972).

In certain embodiments, the pharmaceutically acceptable form is atautomer. As used herein, the term “tautomer” is a type of isomer thatincludes two or more interconvertible compounds resulting from at leastone formal migration of a hydrogen atom and at least one change invalency (e.g., a single bond to a double bond, a triple bond to a singlebond, or vice versa). “Tautomerization” includes prototropic orproton-shift tautomerization, which is considered a subset of acid-basechemistry. “Prototropic tautomerization” or “proton-shifttautomerization” involves the migration of a proton accompanied bychanges in bond order. The exact ratio of the tautomers depends onseveral factors, including temperature, solvent, and pH. Wheretautomerization is possible (e.g., in solution), a chemical equilibriumof tautomers can be reached. Tautomerizations (i.e., the reactionproviding a tautomeric pair) can be catalyzed by acid or base, or canoccur without the action or presence of an external agent. Exemplarytautomerizations include, but are not limited to, keto-to-enol;amide-to-imide; lactam-to-lactim; enamine-to-imine; and enamine-to-(adifferent) enamine tautomerizations. An example of keto-enoltautomerization is the interconversion of pentane-2,4-dione and4-hydroxypent-3-en-2-one tautomers. Another example of tautomerizationis phenol-keto tautomerization. Another example of phenol-ketotautomerization is the interconversion of pyridin-4-ol andpyridin-4(1H)-one tautomers.

As defined herein, the term “Formula (I)” includes(S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinoline-1(2H)-onein its imide tautomer shown below as (I-1) and in its lactim tautomershown below as (I-2):

As defined herein, the term “Formula (I)” includes(S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-onein its imide tautomer shown below as (I-1) and in its lactim tautomershown below as (I-2):

As used herein, and unless otherwise specified, structures depictedherein are also meant to include compounds which differ only in thepresence of one or more isotopically enriched atoms. For example,compounds having the present structures except for the replacement of ahydrogen by a deuterium or tritium, or the replacement of a carbon by¹³C- or ¹⁴C-enriched carbon, or the replacement of a nitrogen by ¹³N- or¹⁵N-enriched nitrogen, or the replacement of an oxygen by ¹⁴O-, ¹⁵O-,¹⁷O- or ¹⁸O-enriched oxygen, or the replacement of a chlorine by ³⁵Cl-,³⁶Cl-, or ³⁷Cl-enriched chlorine, are within the scope of thisdisclosure.

In one embodiment, the compounds of the present disclosure can alsocontain unnatural proportions of atomic isotopes at one or more of atomsthat constitute such compounds. For example, the compounds can beradiolabeled with radioactive isotopes, such as, for example, tritium(³H), iodine-125 (¹²⁵I), or carbon-14 (¹⁴C). Certainisotopically-labeled disclosed compounds (e.g., those labeled with ³Hand ¹⁴C) are useful in compound and/or substrate tissue distributionassays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C) isotopes canallow for case of preparation and detectability. Further, substitutionwith heavier isotopes such as deuterium (i.e., ²H) can afford certaintherapeutic advantages resulting from greater metabolic stability (e.g.,increased in vivo half-life or reduced dosage requirements).Isotopically labeled disclosed compounds can generally be prepared bysubstituting an isotopically labeled reagent for a non-isotopicallylabeled reagent. In some embodiments, provided herein are compounds thatcan also contain unnatural proportions of atomic isotopes at one or moreof atoms that constitute such compounds. All isotopic variations ofcompounds of the present disclosure, whether radioactive or not, areencompassed within the scope of the present disclosure.

As used herein, and unless otherwise specified, the terms “solvent,”“organic solvent,” or “inert solvent” each mean a solvent inert underthe conditions of the reaction being described in conjunction therewith,including, without limitation, benzene, toluene, acetonitrile, ethylacetate, isopropyl acetate, hexane, heptanes, dioxane, tetrahydrofuran(“THF”), dimethylformamide (“DMF”), dimethylacetamide (“DMA”),chloroform, methylene chloride (dichloromethane), diethyl ether,methanol, butanol, methyl t-butyl ether (“MTBE”), 2-butanone (“MEK”),N-methylpyrrolidone (“NMP”), pyridine, and the like. Unless specified tothe contrary, the solvents used in reactions described herein are inertorganic solvents. Unless specified to the contrary, for each gram of alimiting reagent, one cc (or mL) of solvent constitutes a volumeequivalent.

As used herein, and unless otherwise specified, “pharmaceuticallyacceptable carrier” or “pharmaceutically acceptable excipient” includesany and all solvents, dispersion media, coatings, antibacterial andantifungal agents, isotonic and absorption delaying agents and the like.The use of such media and agents for pharmaceutically active substancesis known in the art. Except insofar as any conventional media or agentis incompatible with the active ingredient, its use in the therapeuticcompositions of the present disclosure is contemplated. Supplementaryactive ingredients can also be incorporated into the compositions.

As used herein, and unless otherwise specified. “polymorph” can be usedherein to describe a crystalline material, e.g., a crystalline form. Incertain embodiments. “polymorph” as used herein are also meant toinclude all crystalline and amorphous forms of a compound or a saltthereof, including, for example, crystalline forms, polymorphs,pseudopolymorphs, solvates, hydrates, co-crystals, unsolvated polymorphs(including anhydrates), conformational polymorphs, tautomeric forms,disordered crystalline forms, and amorphous forms, as well as mixturesthereof, unless a particular crystalline or amorphous form is referredto. Compounds of the present disclosure include crystalline andamorphous forms of those compounds, including, for example, crystallineforms, polymorphs, pseudopolymorphs, solvates, hydrates, co-crystals,unsolvated polymorphs (including anhydrates), conformational polymorphs,tautomeric forms, disordered crystalline forms, and amorphous forms ofthe compounds or a salt thereof, as well as mixtures thereof.

As used herein, and unless otherwise specified, a particular form of acompound of Formula (I) described herein (e.g., Form A, B, C, D, E, F,G, H, I, J, or amorphous form of a compound of Formula (I), or mixturesthereof) is meant to encompass a solid form of a compound of Formula(I), or a salt, solvate, or hydrate thereof, among others.

As used herein, and unless otherwise specified, the terms “solid form”and related terms herein refer to a physical form comprising a compoundprovided herein or a salt or solvate or hydrate thereof, which is not ina liquid or a gaseous state. Solid forms can be crystalline, amorphous,disordered crystalline, partially crystalline, and/or partiallyamorphous.

As used herein, and unless otherwise specified, the term “crystalline,”when used to describe a substance, component, or product, means that thesubstance, component, or product is substantially crystalline asdetermined, for example, by X-ray diffraction. See. e.g., Remington: TheScience and Practice of Pharmacy, Lippincott Williams & Wilkins, 21^(st)ed. (2005).

As used herein, and unless otherwise specified, the term “crystallineform.” “crystal form,” and related terms herein refer to the variouscrystalline material comprising a given substance, includingsingle-component crystal forms and multiple-component crystal forms, andincluding, but not limited to, polymorphs, solvates, hydrates,co-crystals and other molecular complexes, as well as salts, solvates ofsalts, hydrates of salts, other molecular complexes of salts, andpolymorphs thereof. In certain embodiments, a crystal form of asubstance can be substantially free of amorphous forms and/or othercrystal forms. In other embodiments, a crystal form of a substance cancontain about 1%, about 2%, about 3%, about 4%, about 5%, about 10%,about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about45% or about 50% of one or more amorphous form(s) and/or other crystalform(s) on a weight and/or molar basis.

Certain crystal forms of a substance can be obtained by a number ofmethods, such as, without limitation, melt recrystallization, meltcooling, solvent recrystallization, recrystallization in confinedspaces, such as, e.g., in nanopores or capillaries, recrystallization onsurfaces or templates, such as, e.g., on polymers, recrystallization inthe presence of additives, such as, e.g., co-crystal counter-molecules,desolvation, dehydration, rapid evaporation, rapid cooling, slowcooling, vapor diffusion, sublimation, grinding, solvent-drop grinding,microwave-induced precipitation, sonication-induced precipitation,laser-induced precipitation, and/or precipitation from a supercriticalfluid. As used herein, and unless otherwise specified, the term“isolating” also encompasses purifying.

Techniques for characterizing crystal forms and amorphous forms caninclude, but are not limited to, thermal gravimetric analysis (TGA),differential scanning calorimetry (DSC), X-ray powder diffractometry(XRPD), single crystal X-ray diffractometry, vibrational spectroscopy,e.g., infrared (IR) and Raman spectroscopy, solid-state nuclear magneticresonance (NMR) spectroscopy, optical microscopy, hot stage opticalmicroscopy, scanning electron microscopy (SEM), electron crystallographyand quantitative analysis, particle size analysis (PSA), surface areaanalysis, solubility studies, and dissolution studies.

As used herein, and unless otherwise specified, the term “peak,” whenused in connection with the spectra or data presented in graphical form(e.g., XRPD, IR. Raman, and NMR spectra), refers to a peak or otherspecial feature that one skilled in the art would recognize as notattributable to background noise. The term “significant peak” refers topeaks at least the median size (e.g., height) of other peaks in thespectrum or data, or at least 1.5. 2, or 2.5 times the background levelin the spectrum or data.

As used herein, and unless otherwise specified, the term “amorphous,”“amorphous form.” and related terms herein mean that the substance,component or product in question is not substantially crystalline asdetermined by X-ray diffraction. In certain embodiments, an amorphousform of a substance can be substantially free of other amorphous formsand/or crystal forms. In certain embodiments, an amorphous form of asubstance can comprise one or more disordered crystalline forms. Inother embodiments, an amorphous form of a substance can contain about1%, about 20/a, about 3%, about 4%, about 5%, about 10%, about 15%,about 20%, about 25%, about 30%, about 35%, about 40%, about 45% orabout 50% of one or more other amorphous forms and/or crystal forms on aweight and/or molar basis. Amorphous forms of a substance can beobtained by a number of methods, as known in the art. Such methodsinclude, but are not limited to, heating, melt cooling, rapid meltcooling, solvent evaporation, rapid solvent evaporation, desolvation,sublimation, grinding, cryo-grinding, spray drying, and freeze drying.

As used herein and unless otherwise specified, a composition that is“substantially free” of a compound means that the composition containsless than about 20 percent by weight, less than about 10 percent byweight, less than about 5 percent by weight, less than about 3 percentby weight, or less than about 1 percent by weight of the compound.

As used herein, and unless otherwise specified, the term “substantiallypure” when used to describe a polymorph, a crystal form, or a solid formof a compound or complex described herein means a solid form of thecompound or complex that comprises a particular polymorph and issubstantially free of other polymorphic and/or amorphous forms of thecompound. A representative substantially pure polymorph comprisesgreater than about 80% by weight of one polymorphic form of the compoundand less than about 20% by weight of other polymorphic and/or amorphousforms of the compound; greater than about 90% by weight of onepolymorphic form of the compound and less than about 10% by weight ofother polymorphic and/or amorphous forms of the compound; greater thanabout 95% by weight of one polymorphic form of the compound and lessthan about 5% by weight of other polymorphic and/or amorphous forms ofthe compound; greater than about 97% by weight of one polymorphic formof the compound and less than about 3% by weight of other polymorphicand/or amorphous forms of the compound; or greater than about 99% byweight of one polymorphic form of the compound and less than about 1% byweight of other polymorphic and/or amorphous forms of the compound.

As used herein, and unless otherwise specified, a crystal form that is“essentially free” of water and/or solvent in the crystal lattice has aquantity of water and/or solvent in the crystal lattice which is, incertain embodiments, approximately near the limit of detection, in otherembodiments, approximately at the limit of detection, and in otherembodiments, approximately below the limit of detection for solventand/or water in the crystal lattice when measured using a conventionalsolid-state analytical technique, e.g., a technique described herein. Incertain embodiments, the solid-state analytical technique used todetermine the quantity of water and/or solvent in the crystal lattice isthermogravimetric analysis. In other embodiments, the solid-stateanalytical technique used to determine the quantity of water and/orsolvent in the crystal lattice is Karl Fischer analysis. In otherembodiments, a crystal form which is “essentially free” of water and/orsolvent in the crystal lattice has a quantity of water and/or solventwhich is less than about 5%, less than about 4%, less than about 3%,less than about 2%, less than about 1%, less than about 0.9%, less thanabout 0.8%, less than about 0.7%, less than about 0.6%, less than about0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%,less than about 0.1%, less than about 0.05%, or less than about 0.01% ofthe total weight of the crystal form.

As used herein, a crystalline or amorphous form that is “pure,” i.e.,substantially free of other crystalline or amorphous forms, containsless than about 10 percent by weight of one or more other crystalline oramorphous form, less than about 5 percent by weight of one or more othercrystalline or amorphous form, less than about 3 percent by weight ofone or more other crystalline or amorphous form, or less than about 1percent by weight of one or more other crystalline or amorphous form.

As used herein, and unless otherwise specified, the term “stable” refersto a compound or composition that does not readily decompose or changein chemical makeup or physical state. A stable composition orformulation provided herein does not significantly decompose undernormal manufacturing or storage conditions. In some embodiments, theterm “stable,” when used in connection with a formulation or a dosageform, means that the active ingredient of the formulation or dosage formremains unchanged in chemical makeup or physical state for a specifiedamount of time and does not significantly degrade or aggregate or becomeotherwise modified (e.g., as determined, for example, by HPLC, FTIR, orXRPD). In some embodiments, about 70 percent or greater, about 80percent or greater, about 90 percent or greater, about 95 percent orgreater, about 98 percent or greater, or about 99 percent or greater ofthe compound remains unchanged after the specified period. In oneembodiment, a polymorph provided herein is stable upon long-term storage(e.g., no significant change in polymorph form after about 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 30, 36, 42, 48, 54, 60, or greaterthan about 60 months).

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75th ed., inside cover, and specificfunctional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in OrganicChemistry. Thomas Sorrell, University Science Books, Sausalito, 1999;Smith and March March's Advanced Organic Chemistry, 5th ed., John Wiley& Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Method of Organic Synthesis, 3rd ed., Cambridge UniversityPress. Cambridge, 1987.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₆ alkyl” is intended toencompass. C₁, C₂. C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅. C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆ alkyl.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to ten carbon atoms (e.g., C₁-C₁₀ alkyl).Whenever it appears herein, a numerical range such as “1 to 10” refersto each integer in the given range; e.g., “1 to 10 carbon atoms” meansthat the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3carbon atoms, etc., up to and including 10 carbon atoms, although thepresent definition also covers the occurrence of the term “alkyl” whereno numerical range is designated. In some embodiments, it is a C₁-C₆alkyl group. In some embodiments, alkyl groups have 1 to 10, 1 to 6, or1 to 3 carbon atoms. Representative saturated straight chain alkylsinclude, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl,-n-pentyl, and -n-hexyl, while saturated branched alkyls include, butare not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl,-isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl,4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, and the like. The alkylis attached to the parent molecule by a single bond. Unless statedotherwise in the specification, an alkyl group is optionally substitutedby one or more of substituents which independently include: acyl, alkyl,alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy,amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl,heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy,cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio,alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate,phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl,sulfonate, urea, —Si(R^(a))₃—, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂,—N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or2), or —O—P(═O)(OR^(a))₂ w % here each R^(a) is independently hydrogen,alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl,and each of these moieties can be optionally substituted as definedherein.

“Perhaloalkyl” refers to an alkyl group in which all of the hydrogenatoms have been replaced with a halogen selected from fluoro, chloro,bromo, and iodo. In some embodiments, all of the hydrogen atoms arm eachreplaced with fluoro. In some embodiments, all of the hydrogen atoms areeach replaced with chloro. Examples of perhaloalkyl groups include —CF₃,—CF₂CF₃, —CF₂CF₂CF₃, —CCl₃, —CFCl₂, —CF₂Cl and the like.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one double bond, and having from two to ten carbon atoms (i.e.,C₂-C₁₀ alkenyl). Whenever it appears herein, a numerical range such as“2 to 10” refers to each integer in the given range; e.g., “2 to 10carbon atoms” means that the alkenyl group can consist of 2 carbonatoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. Incertain embodiments, an alkenyl comprises two to eight carbon atoms. Inother embodiments, an alkenyl comprises two to five carbon atoms (e.g.,C₂-C₅ alkenyl). The alkenyl is attached to the parent molecularstructure by a single bond, for example, ethenyl (i.e., vinyl),prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl,and the like, be one or more carbon-carbon double bonds can be internal(such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples ofC₂₋₄ alkenyl groups include ethenyl (C₂), 1-propenyl (C₃), 2-propenyl(C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄) and the like.Examples of C₂₋₄ alkenyl groups include the aforementioned C₂₋₄ alkenylgroups as well as pentenyl (C₅), pentadienyl (C₅), hexenyl (C₆) and thelike. Additional examples of alkenyl include heptenyl (C₇), octenyl(C₈), octatrienyl (C₈) and the like. Unless stated otherwise in thespecification, an alkenyl group is optionally substituted by one or moresubstituents which independently include: acyl, alkyl, alkenyl, alkynyl,alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido,amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl,heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo,haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio,arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate,silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea,—Si(R^(a))₃—, —OR^(a), —SR^(a). —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein.

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one triple bond, having from two to ten carbon atoms (i.e., C₂-C₁₀alkynyl). Whenever it appears herein, a numerical range such as “2 to10” refers to each integer in the given range; e.g., “2 to 10 carbonatoms” means that the alkynyl group can consist of 2 carbon atoms, 3carbon atoms, etc., up to and including 10 carbon atoms. In certainembodiments, an alkynyl comprises two to eight carbon atoms. In otherembodiments, an alkynyl has two to five carbon atoms (e.g., C₂-C₅alkynyl). The alkynyl is attached to the parent molecular structure by asingle bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl,and the like. Unless stated otherwise in the specification, an alkynylgroup is optionally substituted by one or more substituents whichindependently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl,cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide,carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy,haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio,thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl,sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea,—Si(R^(a))₃—, —OR^(a), —SR^(a). —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R¹)C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein.

The term “alkoxy” refers to the group —O-alkyl, including from 1 to 10carbon atoms of a straight, branched, cyclic configuration andcombinations thereof, attached to the parent molecular structure throughan oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy,cyclopropyloxy, cyclohexyloxy and the like. “Lower alkoxy” refers toalkoxy groups containing one to six carbons. In some embodiments, C₁-C₄alkoxy is an alkoxy group which encompasses both straight and branchedchain alkyls of from 1 to 4 carbon atoms. Unless stated otherwise in thespecification, an alkoxy group is optionally substituted by one or moresubstituents which independently include: acyl, alkyl, alkenyl, alkynyl,alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido,amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl,heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo,haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio,arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate,silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea,—Si(R^(a))₃—, —OR, —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein. The terms“alkenoxy” and “alkynoxy” mirror the above description of “alkoxy”wherein the prefix “alk” is replaced with “alken” or “alkyn”respectively, and the parent “alkenyl” or “alkynyl” terms are asdescribed herein.

The term “alkoxycarbonyl” refers to a group of the formula(alkoxy)(C═O)— attached to the parent molecular structure through thecarbonyl carbon having from 1 to 10 carbon atoms. Thus a C₁-C₆alkoxycarbonyl group is an alkoxy group having from 1 to 6 carbon atomsattached through its oxygen to a carbonyl linker. The C₁-C₆ designationdoes not include the carbonyl carbon in the atom count. “Loweralkoxycarbonyl” refers to an alkoxycarbonyl group wherein the alkylportion of the alkoxy group is a lower alkyl group. In some embodiments,C₁-C₄ alkoxy is an alkoxy group which encompasses both straight andbranched chain alkoxy groups of from 1 to 4 carbon atoms. Unless statedotherwise in the specification, an alkoxycarbonyl group is optionallysubstituted by one or more substituents which independently include:acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl,aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate,carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester,ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo,phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl,sulfonamidyl, sulfoxyl, sulfonate, urea, —Si(R^(a))₃—, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂,—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein. The terms“alkenoxycarbonyl” and “alkynoxycarbonyl” mirror the above descriptionof “alkoxycarbonyl” w % herein the prefix “alk” is replaced with “alken”or “alkyn” respectively, and the parent “alkenyl” or “alkynyl” terms areas described herein.

“Acyl” refers to R—C(O)— groups such as, but not limited to,(alkyl)-C(O)—, (alkenyl)-C(O)—, (alkynyl)-C(O)—. (aryl)-C(O)—,(cycloalkyl)-C(O)—, (heteroaryl)-C(O)—, (heteroalkyl)-C(O)—, and(heterocycloalkyl)-C(O)—, wherein the group is attached to the parentmolecular structure through the carbonyl functionality. In someembodiments, it is a C₁-C₁₀ acyl radical which refers to the totalnumber of chain or ring atoms of the, for example, alkyl, alkenyl,alkynyl, aryl, cyclohexyl, heteroaryl or heterocycloalkyl portion plusthe carbonyl carbon of acyl. For example, a C₄-acyl has three other ringor chain atoms plus carbonyl. If the R radical is heteroaryl orheterocycloalkyl, the hetero ring or chain atoms contribute to the totalnumber of chain or ring atoms. Unless stated otherwise in thespecification, the “R” of an acyloxy group can be optionally substitutedby one or more substituents which independently include: acyl, alkyl,alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy,amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl,heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy,cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio,alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate,phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl,sulfonate, urea, —Si(R^(a))₃—, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂,N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or2), or —O—P(═O)(OR^(a))₂ where each R^(a) is independently hydrogen,alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl,and each of these moieties can be optionally substituted as definedherein.

“Acyloxy” refers to a R(C═O)O— radical wherein “R” can be alkyl,alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl,cyclohexyl, heteroaryl or heterocycloalkyl, which are as describedherein. The acyloxy group is attached to the parent molecular structurethrough the oxygen functionality. In some embodiments, an acyloxy groupis a C₁-C₄ acyloxy radical which refers to the total number of chain orring atoms of the alkyl, alkenyl, alkynyl, aryl, cyclohexyl, heteroarylor heterocycloalkyl portion of the acyloxy group plus the carbonylcarbon of acyl, i.e., a C₄-acyloxy has three other ring or chain atomsplus carbonyl. If the R radical is heteroaryl or heterocycloalkyl, thehetero ring or chain atoms contribute to the total number of chain orring atoms. Unless stated otherwise in the specification, the “R” of anacyloxy group is optionally substituted by one or more substituentswhich independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy,alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino,imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy,haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio,thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl,sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea.—Si(R^(a))₃—, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl and each of thesemoieties can be optionally substituted as defined herein.

“Amino” or “amine” refers to a —N(R^(b))₂, —N(R^(b))R^(b)—, or—R^(b)N(R^(b))R^(b)— radical group, where each R^(b) is independentlyselected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl(bonded through a chain carbon), cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocycloalkyl (bonded through a ring carbon),heterocycloalkylalkyl, heteroaryl (bonded through a ring carbon) orheteroarylalkyl, unless stated otherwise in the specification, each ofwhich moiety can itself be optionally substituted as described herein.When a —N(R^(b))₂ group has two R^(b) other than hydrogen, they can becombined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-memberedring. For example, —N(R^(b))₂ is meant to include, but not be limitedto, 1-pyrrolidinyl and 4-morpholinyl. Unless stated otherwise in thespecification, an amino group is optionally substituted by one or moresubstituents which independently include: acyl, alkyl, alkenyl, alkynyl,alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido,amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl,heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo,haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio,arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate,silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea.—Si(R^(a))₃—, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a). —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein.

The terms “amine” and “amino” also refer to N-oxides of the groups—N⁺(H)(R^(a))O⁻, and —N⁺(R^(a))(R^(a))O—, R^(a) as described above,where the N-oxide is bonded to the parent molecular structure throughthe N atom. N-oxides can be prepared by treatment of the correspondingamino group with, for example, hydrogen peroxide orm-chloroperoxybenzoic acid. The person skilled in the art is familiarwith reaction conditions for carrying out the N-oxidation.

“Amide” or “amido” refers to a chemical moiety with formula—C(O)N(R^(b))₂ or —NR^(b)C(O)R^(a), where R^(b) is independentlyselected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl(bonded through a chain carbon), cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocycloalkyl (bonded through a ring carbon),heterocycloalkylalkyl, heteroaryl (bonded through a ring carbon) orheteroarylalkyl, unless stated otherwise in the specification, each ofwhich moiety can itself be optionally substituted as described herein.In some embodiments, this radical is a C₁-C₄ amido or amide radical,which includes the amide carbonyl in the total number of carbons in theradical. When a —C(O)N(R^(b))₂ has two R^(b) other than hydrogen, theycan be combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or7-membered ring. For example, N(R^(b))₂ portion of a —C(O)N(R^(b))₂radical is meant to include, but not be limited to, I-pyrrolidinyl and4-morpholinyl. Unless stated otherwise in the specification, an amidoR^(b) group is optionally substituted by one or more substituents whichindependently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl,cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide,carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy,haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio,thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl,sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea.—Si(R^(a))₃—, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a).—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a)), N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein.

The term “amide” or “amido” is inclusive of an amino acid or a peptidemolecule. Any amine, hydroxy, or carboxyl side chain on the compoundsdescribed herein can be transformed into an amide group. The proceduresand specific groups to make such amides are known to those of skill inthe art and can readily be found in reference sources such as Greene andWuts. Protective Groups in Organic Synthesis, 3rd Ed., John Wiley &Sons. New York, N.Y., 1999, which is incorporated herein by reference inits entirety.

“Amidino” refers to both the —C(═NR^(b))N(R^(b))₂ and—N(R^(b))—C(═NR^(b))— radicals, where each R^(b) is independentlyselected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl(bonded through a chain carbon), cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocycloalkyl (bonded through a ring carbon),heterocycloalkylalkyl, heteroaryl (bonded through a ring carbon) orheteroarylalkyl, unless stated otherwise in the specification, each ofwhich moiety can itself be optionally substituted as described herein.

“Aromatic” or “aryl” refers to a radical with six to ten ring atoms(e.g., C₆-C₁₀ aromatic or C₆-C₁₀ aryl) which has at least one ringhaving a conjugated pi electron system which is carbocyclic (e.g.,phenyl, fluorenyl, and naphthyl). For example, bivalent radicals formedfrom substituted benzene derivatives and having the free valences atring atoms are named as substituted phenylene radicals. In otherembodiments, bivalent radicals derived from univalent polycyclichydrocarbon radicals whose names end in “-yl” by removal of one hydrogenatom from the carbon atom with the free valence are named by adding“-idene” to the name of the corresponding univalent radical. e.g., anaphthyl group with two points of attachment is termed naphthylidene.Whenever it appears herein, a numerical range such as “6 to 10 aryl”refers to each integer in the given range; e.g., “6 to 10 ring atoms”means that the aryl group can consist of 6 ring atoms, 7 ring atoms,etc., up to and including 10 ring atoms. The term includes monocyclic orfused-ring polycyclic (i.e., rings which share adjacent pairs of ringatoms) groups. Unless stated otherwise in the specification, an arylmoiety can be optionally substituted by one or more substituents whichindependently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl,cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide,carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy,haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio,thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl,sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea,—Si(R^(a))₃—, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein.

“Aralkyl” or “arylalkyl” refers to an (aryl)alkyl-radical where aryl andalkyl are as disclosed herein and which are optionally substituted byone or more of the substituents described as suitable substituents foraryl and alkyl respectively. The “aralkyl/arylalkyl” is bonded to theparent molecular structure through the alkyl group. The terms“aralkenyl/arylalkenyl” and “aralkynyl/arylalkynyl” mirror the abovedescription of “aralkyl/arylalkyl” wherein the “alkyl” is replaced with“alkenyl” or “alkynyl” respectively, and the “alkenyl” or “alkynyl”terms are as described herein.

“Azide” refers to a —N₃ radical.

“Carbamate” refers to any of the following radicals: —O—(C═O)—N(R^(b))—,—O—(C═O)—N(R^(b))₂, —N(R^(b))—(C═O)—O—, and —N(R^(b))(C═O)—OR^(b),wherein each R^(b) is independently selected from alkyl, alkenyl,alkynyl, haloalkyl, heteroalkyl (bonded through a chain carbon),cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bondedthrough a ring carbon), heterocycloalkylalkyl, heteroaryl (bondedthrough a ring carbon) or heteroarylalkyl, unless stated otherwise inthe specification, each of which moiety can itself be optionallysubstituted as described heroin.

“Carbonate” refers to a —O—(C═O)—O— radical.

“Carbonyl” refers to a —(C═O)— radical.

“Carboxaldehyde” refers to a —(C═O)H radical.

“Carboxyl” refers to a —(C═O)OH radical.

“Cyano” refers to a —CN radical.

“Cycloalkyl” and “carbocyclyl” each refer to a monocyclic or polycyclicradical that contains only carbon and hydrogen, and can be saturated orpartially unsaturated. Partially unsaturated cycloalkyl groups can betermed “cycloalkenyl” if the carbocycle contains at least one doublebond, or “cycloalkynyl” if the carbocycle contains at least one triplebond. Cycloalkyl groups include groups having from 3 to 10 ring atoms(i.e., C₃-C₁₀ cycloalkyl). Whenever it appears herein, a numerical rangesuch as “3 to 10” refers to each integer in the given range; e.g., “3 to10 carbon atoms” means that the cycloalkyl group can consist of 3 carbonatoms, 4 carbon atoms, 5 carbon atoms, etc., up to and including 10carbon atoms. The term “cycloalkyl” also includes bridged andspiro-fused cyclic structures containing no heteroatoms. The term alsoincludes monocyclic or fused-ring polycyclic (i.e., rings which shareadjacent pairs of ring atoms) groups. In some embodiments, it is a C₃-C₈cycloalkyl radical. In some embodiments, it is a C₃-C₅cycloalkylradical. Illustrative examples of cycloalkyl groups include, but are notlimited to the following moieties: C₃₋₆ carbocyclyl groups include,without limitation, cyclopropyl (C₃), cyclobutyl (C₄), cyclopentyl (C₅),cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexcnyl (C₆), cyclohexadienyl(C₆) and the like. Examples of C₃₋₈ carbocyclyl groups include theaforementioned C₃₋₆ carbocyclyl groups as well as cycloheptyl (C₇),cycloheptadienyl (C₇), cycloheptatrienyl (C₇), cyclooctyl (C₈),bicyclo[2,2,1]heptanyl, bicyclo[2,2,2]octanyl, and the like. Examples ofC₃₋₁₀ carbocyclyl groups include the aforementioned C₃₋₈ carbocyclylgroups as well as octahydro-1H-indenyl, decahydronaphthalenyl,spiro[4,5]decanyl and the like. Unless stated otherwise in thespecification, a cycloalkyl group is optionally substituted by one ormore substituents which independently include: acyl, alkyl, alkenyl,alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino,amido, amidino, imino, azide, carbonate, carbamate, carbonyl,heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy,cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio,alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate,phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl,sulfonate, urea. —Si(R^(a))₃—, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂,N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or2), or —O—P(═O)(OR^(a))₂ where each R^(a) is independently hydrogen,alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl,and each of these moieties can be optionally substituted as definedherein.

“Ester” refers to a radical of formula —COOR, where R is selected fromalkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bonded through a chaincarbon), cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl(bonded through a ring carbon), heterocycloalkylalkyl, heteroaryl(bonded through a ring carbon) or heteroarylalkyl. Any amine, hydroxy,or carboxyl side chain on the compounds described herein can beesterified. The procedures and specific groups to make such esters areknown to those of skill in the art and can readily be found in referencesources such as Greene and Wuts, Protective Groups in Organic Synthesis,3rd Ed., John Wiley & Sons, New York, N.Y. 1999, which is incorporatedherein by reference in its entirety. Unless stated otherwise in thespecification, an ester group can be optionally substituted by one ormore substituents which independently include: acyl, alkyl, alkenyl,alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino,amido, amidino, imino, azide, carbonate, carbamate, carbonyl,heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy,cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio,alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate,phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl,sulfonate, urea, —Si(R^(a))₃—, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂,N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or2), or —O—P(═O)(OR^(a))₂ where each R^(a) is independently hydrogen,alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl,and each of these moieties can be optionally substituted as definedherein.

“Ether” refers to a —R^(b)—O—R^(b)— radical where each R isindependently selected from hydrogen, alkyl, alkenyl, alkynyl,haloalkyl, heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon) or heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein.

“Halo”, “halide”, or, alternatively, “halogen” means fluoro, chloro,bromo or iodo. The terms “haloalkyl,” “haloalkenyl,” “haloalkynyl” and“haloalkoxy” include alkyl, alkenyl, alkynyl and alkoxy structures thatare substituted with one or more halo groups or with combinationsthereof. For example, the terms “fluoroalkyl” and “fluoroalkoxy” includehaloalkyl and haloalkoxy groups, respectively, in which the halo isfluorine, such as, but not limited to, trifluoromethyl, difluoromethyl,2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. Eachof the alkyl, alkenyl, alkynyl and alkoxy groups are as defined hereinand can be optionally further substituted as defined herein.

“Heteroalkyl”, “heteroalkenyl” and “heteroalkynyl” include alkyl,alkenyl and alkynyl radicals, respectively, which have one or moreskeletal chain atoms selected from an atom other than carbon, e.g.,oxygen, nitrogen, sulfur, phosphorus or combinations thereof. Anumerical range can be given, e.g., C₁-C₄ heteroalkyl which refers tothe chain length in total, which in this example is 4 atoms long. Forexample, a —CH₂OCH₂CH₃ radical is referred to as a “C₄” heteroalkyl,which includes the heteroatom center in the atom chain lengthdescription. Connection to the parent molecular structure can be througheither a heteroatom or a carbon in the heteroalkyl chain. For example,an N-containing heteroalkyl moiety refers to a group in which at leastone of the skeletal atoms is a nitrogen atom. One or more heteroatom(s)in the heteroalkyl radical can be optionally oxidized. One or morenitrogen atoms, if present, can also be optionally quaternized. Forexample, heteroalkyl also includes skeletal chains substituted with oneor more nitrogen oxide (—O—) substituents. Exemplary heteroalkyl groupsinclude, without limitation, ethers such as methoxyethanyl(—CH₂CH₂OCH₃), ethoxymethanyl (—CH₂OCH₂CH₃), (methoxymethoxy)ethanyl(—CH₂CH₂OCH₂OCH₃). (methoxymethoxy)methanyl (—CH₂OCH₂OCH₃) and(methoxyethoxy)methanyl (—CH₂OCH₂CH₂OCH₃) and the like; amines such as—CH₂CH₂NHCH₃, —CH₂CH₂N(CH₃)₂, —CH₂NHCH₂CH₃, —CH₂N(CH₂CH₃)(CH₃) and thelike. Heteroalkyl, heteroalkenyl, and heteroalkynyl groups can each beoptionally substituted by one or more substituents which independentlyinclude: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl,aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate,carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester,ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo,phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl,sulfonamidyl, sulfoxyl, sulfonate, urea, —Si(R^(a))₃—, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂,—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)NR^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein.

“Heteroaryl” or, alternatively, “heteroaromatic” refers to a refers to aradical of a 5-18 membered monocyclic or polycyclic (e.g., bicyclic ortricyclic) aromatic ring system (e.g., having 6, 10 or 14 π (pi)electrons shared in a cyclic army) having ring carbon atoms and 1-6 ringheteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen, phosphorousand sulfur (“5-18 membered heteroaryl”). Heteroaryl polycyclic ringsystems can include one or more heteroatoms in one or both rings.Whenever it appears herein, a numerical range such as “5 to 18” refersto each integer in the given range; e.g., “5 to 18 ring atoms” meansthat the heteroaryl group can consist of 5 ring atoms, 6 ring atoms,etc., up to and including 18 ring atoms. For example, bivalent radicalsderived from univalent heteroaryl radicals whose names end in “-yl” byremoval of one hydrogen atom from the atom with the free valence arenamed by adding “-idene” to the name of the corresponding univalentradical, e.g., a pyridyl group with two points of attachment is apyridylidene.

For example, an N-containing “heteroaromatic” or “heteroaryl” moietyrefers to an aromatic group in which at least one of the skeletal atomsof the ring is a nitrogen atom. One or more heteroatom(s) in theheteroaryl radical can be optionally oxidized. One or more nitrogenatoms, if present, can also be optionally quatemized. Heteroaryl alsoincludes ring systems substituted with one or more nitrogen oxide (—O—)substituents, such as pyridinyl N-oxides. The heteroaryl is attached tothe parent molecular structure through any atom of the ring(s).

“Heteroaryl” also includes ring systems wherein the heteroaryl ring, asdefined above, is fused with one or more aryl groups wherein the pointof attachment to the parent molecular structure is either on the aryl oron the heteroaryl ring, or wherein the heteroaryl ring, as definedabove, is fused with one or more cycloalkyl or heterocycyl groupswherein the point of attachment to the parent molecular structure is onthe heteroaryl ring. For polycyclic heteroaryl groups wherein one ringdoes not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl andthe like), the point of attachment to the parent molecular structure canbe on either ring, i.e., either the ring bearing a heteroatom (e.g.,2-indolyl) or the ring that does not contain a heteroatom (e.g.,5-indolyl). In some embodiments, a heteroaryl group is a 5-10 memberedaromatic ring system having ring carbon atoms and 1-4 ring heteroatomsprovided in the aromatic ring system, wherein each heteroatom isindependently selected from nitrogen, oxygen, phosphorous, and sulfur(“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group isa 5-8 membered aromatic ring system having ring carbon atoms and 1-4ring heteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen, phosphorous,and sulfur (“5-10 membered heteroaryl”). In some embodiments, aheteroaryl group is a 5-6 membered aromatic ring system having ringcarbon atoms and 1-4 ring heteroatoms provided in the aromatic ringsystem, wherein each heteroatom is independently selected from nitrogen,oxygen, phosphorous, and sulfur (“5-6 membered heteroaryl”). In someembodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatomsselected from nitrogen, oxygen, phosphorous, and sulfur. In someembodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatomsselected from nitrogen, oxygen, phosphorous, and sulfur. In someembodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selectedfrom nitrogen, oxygen, phosphorous, and sulfur.

Examples of heteroaryls include, but are not limited to, azepinyl,acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl,benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl,benzo[b][4,1]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranyl,benzofuranonyl, benzofurazanyl, benzothiazolyl, benzothienyl(benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,6,7-dihydro-5H-benzo[6,7]cyclohcpta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furazanyl, furanonyl, furo[3,2-c]pyridinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hcxahydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hcxahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl,5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, ptridinyl,purinyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl,pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl,pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl,quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,thiapyranyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e.,thienyl). Unless stated otherwise in the specification, a heteroarylmoiety is optionally substituted by one or more substituents whichindependently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl,cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide,carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy,haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio,thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl,sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea.—Si(R^(a))₃, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a).—C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl and each of thesemoieties can be optionally substituted as defined herein.

“Heterocyclyl”, “heterocycloalkyl” or “heterocarbocyclyl” each refer toany 3- to 18-membered non-aromatic radical monocyclic or polycyclicmoiety comprising at least one heteroatom selected from nitrogen,oxygen, phosphorous and sulfur. A heterocyclyl group can be amonocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein thepolycyclic ring systems can be a fused, bridged or spiro ring system.Heterocyclyl polycyclic ring systems can include one or more heteroatomsin one or both rings. A heterocyclyl group can be saturated or partiallyunsaturated. Partially unsaturated heterocycloalkyl groups can be termed“heterocycloalkenyl” if the heterocyclyl contains at least one doublebond, or “heterocycloalkynyl” if the heterocyclyl contains at least onetriple bond. Whenever it appears herein, a numerical range such as “5 to18” refers to each integer in the given range. e.g., “5 to 18 ringatoms” means that the heterocyclyl group can consist of 5 ring atoms, 6ring atoms, etc., up to and including 18 ring atoms. For example,bivalent radicals derived from univalent heterocyclyl radicals whosenames end in “-yl” by removal of one hydrogen atom from the atom withthe free valence are named by adding “-idene” to the name of thecorresponding univalent radical, e.g., a piperidine group with twopoints of attachment is a piperidylidene.

An N-containing heterocyclyl moiety refers to an non-aromatic group inwhich at least one of the ring atoms is a nitrogen atom. Theheteroatom(s) in the heterocyclyl radical can be optionally oxidized.One or more nitrogen atoms, if present, can be optionally quatemized.Heterocyclyl also includes ring systems substituted with one or morenitrogen oxide (—O—) substituents, such as piperidinyl N-oxides. Theheterocyclyl is attached to the parent molecular structure through anyatom of any of the ring(s).

“Heterocyclyl” also includes ring systems wherein the heterocycyl ring,as defined above, is fused with one or more carbocycyl groups whereinthe point of attachment is either on the carbocycyl or heterocyclylring, or ring systems wherein the heterocyclyl ring, as defined above,is fused with one or more aryl or heteroaryl groups, wherein the pointof attachment to the parent molecular structure is on the heterocyclylring. In some embodiments, a heterocyclyl group is a 3-10 memberednon-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, phosphorous and sulfur (“3-10 membered heterocyclyl”).In some embodiments, a heterocyclyl group is a 5-8 membered non-aromaticring system having ring carbon atoms and 1-4 ring heteroatoms, whereineach heteroatom is independently selected from nitrogen, oxygen,phosphorous and sulfur (“5-8 membered heterocyclyl”). In someembodiments, a heterocyclyl group is a 5-6 membered non-aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms, wherein eachheteroatom is independently selected from nitrogen, oxygen, phosphorousand sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen,oxygen phosphorous and sulfur. In some embodiments, the 5-6 memberedheterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen,phosphorous and sulfur. In some embodiments, the 5-6 memberedheterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen,phosphorous and sulfur.

Exemplary 3-membered heterocyclyls containing 1 heteroatom include,without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-memberedheterocyclyls containing 1 heteroatom include, without limitation,azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclylscontaining 1 heteroatom include, without limitation, tetrahydrofuranyl,dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl,dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary 5-memberedheterocyclyls containing 2 heteroatoms include, without limitation,dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-memberedheterocyclyls containing 3 heteroatoms include, without limitation,triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-memberedheterocyclyl groups containing 1 heteroatom include, without limitation,piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary6-membered heterocyclyl groups containing 2 heteroatoms include, withoutlimitation, piperazinyl, morpholinyl, dithianyl, dioxanyl, andtriazinanyl. Exemplary 7-membered heterocyclyl groups containing 1heteroatom include, without limitation, azepanyl, oxepanyl andthiepanyl. Exemplary 8-membered heterocyclyl groups containing 1heteroatom include, without limitation, azocanyl, oxccanyl andthiocanyl. Exemplary bicyclic heterocyclyl groups include, withoutlimitation, indolinyl, isoindolinyl, dihydrobenzofuranyl,dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl,tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl,octahydroisochromenyl, decahydronaphthyridinyl,decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl,phthalimidyl, naphthalimidyl, chromanyl, chromenyl,1H-benzo[e][1.4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl,5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl,5,7-dihydro-4H-thieno[2,3-c]pyranyl,2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl,4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl,4,5,6,7-tetra-hydrofuro[3,2-c]pyridinyl,4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl,1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.

Unless stated otherwise, heterocyclyl moieties are optionallysubstituted by one or more substituents which independently include:acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl,aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate,carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester,ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo,phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl,sulfonamidyl, sulfoxyl, sulfonate, urea, —Si(R^(a))₃—, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂,—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂,where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl and each of thesemoieties can be optionally substituted as defined herein.

“Nitro” refers to the —NO₂ radical.

“Phosphate” refers to a —O—P(═O)(OR^(b))₂ radical, where each R^(b) isindependently selected from hydrogen, alkyl, alkenyl, alkynyl,haloalkyl, heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon) or heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein. In some embodiments, when R^(a) is hydrogen anddepending on the pH, the hydrogen can be replaced by an appropriatelycharged counter ion.

“Imino” refers to the “—(C═N)—R^(b)” radical where R^(b) is selectedfrom hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bondedthrough a chain carbon), cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocycloalkyl (bonded through a ring carbon), heterocycloalkylalkyl,heteroaryl (bonded through a ring carbon) or heteroarylalkyl, unlessstated otherwise in the specification, each of which moiety can itselfbe optionally substituted as described herein.

“Phosphonate” refers to a —O—P(═O)(R^(b))(OR^(b)) radical, where eachR^(b) is independently selected from hydrogen, alkyl, alkenyl, alkynyl,haloalkyl, heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon) or heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein. In some embodiments, when R^(a) is hydrogen anddepending on the pH, the hydrogen can be replaced by an appropriatelycharged counter ion.

“Phosphinate” refers to a —P(═O)(R^(b))(OR^(b)) radical, where eachR^(b) is independently selected from hydrogen, alkyl, alkenyl, alkynyl,haloalkyl, heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon) or heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein. In some embodiments, when R^(a) is hydrogen anddepending on the pH, the hydrogen can be replaced by an appropriatelycharged counter ion.

As used herein, the terms “substituted” or “substitution” mean that atleast one hydrogen present on a group atom (e.g., a carbon or nitrogenatom) is replaced with a permissible substituent, e.g., a substituentwhich upon substitution for the hydrogen results in a stable compound,e.g., a compound which does not spontaneously undergo transformationsuch as by rearrangement, cyclization, elimination, or other reaction.Unless otherwise indicated, a “substituted” group can have a substituentat one or more substitutable positions of the group, and when more thanone position in any given structure is substituted, the substituent iseither the same or different at each position. Substituents include oneor more group(s) individually and independently selected from acyl,alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl,aryloxy, amino, amido, azide, carbonate, carbonyl, heteroalkyl,heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo,haloalkoxy, haloalkyl, ester, mercapto, thio, alkylthio, arylthio,thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl,sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea,—Si(R^(a))₃. —OR^(a). —SR^(a), —OC(O)—R^(a). —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a). —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), —O—P(═O)(OR^(a))₂,where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl and each of thesemoieties can be optionally substituted as defined herein. For example, acycloalkyl substituent can have a halide substituted at one or more ringcarbons, and the like. The protecting groups that can form theprotective derivatives of the above substituents are known to those ofskill in the art and can be found in references such as Greene and Wuts,above.

“Silyl” refers to a —Si(R^(b))₃, radical where each R^(b) isindependently selected from alkyl, alkenyl, alkynyl, haloalkyl,heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon) or heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein.

“Sulfanyl”, “sulfide”, and “thio” each refer to the radical —S—R^(b),wherein R^(b) is selected from alkyl, alkenyl, alkynyl, haloalkyl,heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon) or heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein. For instance, an “alkylthio” refers to the“alkyl-S—” radical, and “arylthio” refers to the “aryl-S—” radical, eachof which are bound to the parent molecular group through the S atom. Theterms “sulfide”, “thiol”, “mercapto”, and “mercaptan” can also eachrefer to the group —R^(b)SH.

“Sulfinyl” or “sulfoxide” refers to the —S(O)—R^(b) radical, wherein for“sulfinyl”, R^(b) is H and for “sulfoxide”. R^(b) is selected fromalkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bonded through a chaincarbon), cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl(bonded through a ring carbon), heterocycloalkylalkyl, heteroaryl(bonded through a ring carbon) or heteroarylalkyl, unless statedotherwise in the specification, each of which moiety can itself beoptionally substituted as described herein.

“Sulfonyl” or “sulfone” refers to the —S(O₂)—R^(b) radical, whereinR^(b) is selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon) or heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein.

“Sulfonamidyl” or “sulfonamido” refers to the following radicals:—S(═O)₂—N(R^(b))₂, —N(R^(b))—S(═O)₂—R^(b), —S(═O)₂—N(R^(b))—, or—N(R^(b))—S(═O)₂, where each R^(b) is independently selected fromhydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bondedthrough a chain carbon), cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocycloalkyl (bonded through a ring carbon), heterocycloalkylalkyl,heteroaryl (bonded through a ring carbon) or heteroarylalkyl, unlessstated otherwise in the specification, each of which moiety can itselfbe optionally substituted as described herein. The R^(b) groups in—S(═O)₂—N(R^(b))₂ can be taken together with the nitrogen to which theyare attached to form a 4-, 5-, 6-, or 7-membered heterocyclyl ring. Insome embodiments, the term designates a C₁-C₄ sulfonamido, wherein eachR^(b) in the sulfonamido contains 1 carbon, 2 carbons, 3 carbons, or 4carbons total.

“Sulfoxyl” or “sulfoxide” refers to a —S(═O)₂OH radical.

“Sulfonate” refers to a —S(═O)₂—OR^(b) radical, wherein R^(b) isselected from alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bondedthrough a chain carbon), cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocycloalkyl (bonded through a ring carbon), heterocycloalkylalkyl,heteroaryl (bonded through a ring carbon) or heteroarylalkyl, unlessstated otherwise in the specification, each of which moiety can itselfbe optionally substituted as described herein.

“Thiocarbonyl” refers to a —(C═S)— radical.

“Urea” refers to a —N(R^(b))—(C═O)—N(R^(b))₂ or—N(R^(b))—(C═O)—N(R^(b))— radical, where each R^(b) is independentlyselected from alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bondedthrough a chain carbon), cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocycloalkyl (bonded through a ring carbon), heterocycloalkylalkyl,heteroaryl (bonded through a ring carbon) or heteroarylalkyl, unlessstated otherwise in the specification, each of which moiety can itselfbe optionally substituted as described herein.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left, e.g., —CH₂O— is equivalent to —OCH₂—.

II. Compounds, Compositions, and Methods of Preparing

In one embodiment, provided herein are polymorphic forms of a compoundof Formula (I):

herein referred to as Form A, Form B, Form C, Form D, Form E, Form F,Form G, Form H, Form I, Form J, or an amorphous form of a compound ofFormula (I), or a salt, solvate, or hydrate thereof, or a mixture of twoor more thereof. In one embodiment, the polymorphic form of a compoundof Formula (I) can be a crystalline form, a partially crystalline form,an amorphous form, or a mixture of crystalline form(s) and/or amorphousform(s).

In one embodiment, the polymorph provided herein is Form A, Form B, FormC, Form D, Form E, Form F, Form G, Form H, Form I, Form J, or anamorphous form of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or hydrate thereof, or a mixture of two ormore thereof. In one embodiment, the polymorph provided herein is FormB, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J. or anamorphous form of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or hydrate thereof. In one embodiment, thepolymorph provided herein is Form A, Form B, Form C. Form D, Form E,Form F, Form G, Form H, Form I, Form J, or an amorphous form of acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or hydrate thereof, or a mixture of two or more thereof, which issubstantially pure. In one embodiment, a polymorph provided herein isthermally stable. In one embodiment, a polymorph provided herein isstable upon long-term storage (e.g., no significant change in polymorphform after about 1, about 2, about 3, about 4, about 5, about 6, about7, about 8, about 9, about 10, about 11, about 12, about 18, about 24,about 30, about 36, about 42, about 48, about 54, about 60, or greaterthan about 60 months). In one embodiment, after storage for a certainperiod of time, less than about 20%, less than about 10%, less thanabout 9%, less than about 8%, less than about 7%₀, less than about 6%,less than about 5%, less than about 4/%, less than about 3%, less thanabout 2%, or less than about 1% w/w of a polymorph provided hereinconverts to other polymorph(s).

In certain embodiments, a polymorph provided herein is polymorph Form Cof a compound of Formula (I). In certain embodiments, provided herein isa solid form of a compound of Formula (I) comprising Form C of acompound of Formula (I). In certain embodiments, provided herein is asolid form of a compound of Formula (I) comprising Form C of a compoundof Formula (I), which is substantially pure. In one embodiment, Form Ccan be characterized by having X-ray powder diffraction (XRPD) peaks atabout 10.4, about 13.3, and about 24.3 degrees 2θ. In certainembodiments, Form C is characterized by having differential scanningcalorimetry (DSC) comprising an endotherm at about 208° C. In certainembodiments, Form C can be characterized by thermogravimetric analysiswhere the % weight loss observed is about 1.7% at about 80° C. and about0.2% at about 190° C.

In one embodiment, a non-Form C polymorph is a solid form of a compoundof Formula (I), or a salt, solvate, or hydrate thereof (e.g., acrystalline form, an amorphous form, or a mixture of crystalline form(s)and/or amorphous form(s)), which is not polymorph Form C of a compoundof Formula (I). In one embodiment, a non-Form C polymorph is Form A,Form B, Form D, Form E, Form F, Form G, Form H, Form I, Form J. or anamorphous form of a compound of Formula (I), or a salt, solvate, orhydrate thereof, or a mixture of two or more thereof. In one embodiment,a non-Form C polymorph can comprise at least 50% by weight polymorphForm A of a compound of Formula (I). In one embodiment, a non-Form Cpolymorph (e.g., Form A or Form B) can be obtained from a compositioncomprising Form C.

In certain embodiments, a salt of a compound of Formula (I) providedherein is a salt derived from L-tartaric acid, p-toluenesulfonic acid,D-glucaronic acid, ethane-1,2-disulfonic acid (EDSA),2-naphthalenesulfonic acid (NSA), hydrochloric acid (HCl), hydrobromicacid (HBr), citric acid, naphthalene-1,5-disulfonic acid (NDSA),DLI-mandelic acid, fumaric acid, sulfuric acid, maleic acid,methanesulfonic acid (MSA), benzenesulfonic acid (BSA), ethanesulfonicacid (ESA), L-malic acid, phosphoric acid, or aminoethanesulfonic acid(taurine). In certain embodiments, a salt of a compound of Formula (I)provided herein is a mono-acid salt or a bis-acid salt. In certainembodiments, a salt of a compound of Formula (I) provided herein is anHCl salt (e.g., a mono-HCl salt or a bis-HCl salt), or a solvate orhydrate thereof. In certain embodiments, a salt, solvate, or hydrate ofa compound of Formula (I) provided herein is a crystalline material, apartially crystalline material, or an amorphous material or a mixture ofone or more crystalline form(s) and/or amorphous form(s).

In one embodiment, provided herein is a composition comprising acompound of Formula (I):

or a pharmaceutically acceptable salt, solvate, or hydrate thereof, andone or more pharmaceutically acceptable excipients.

In one embodiment, the composition comprises polymorph Form C. In oneembodiment, the composition comprises a mixture of polymorph Form C andat least one non-Form C polymorph of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or hydrate thereof. Forexample, in certain embodiments, the composition can comprise polymorphForm C and polymorph Form A. In other embodiments, the composition cancomprise polymorph Form C and polymorph Form B. In other embodiments,the composition can comprise polymorph Form C and polymorph Form D. Inother embodiments, the composition can comprise polymorph Form C andpolymorph Form E. In other embodiments, the composition can comprisepolymorph Form C and polymorph Form F. In other embodiments, thecomposition can comprise polymorph Form C and polymorph Form G. In otherembodiments, the composition can comprise polymorph Form C and polymorphForm H. In other embodiments, the composition can comprise polymorphForm C and polymorph Form I. In other embodiments, the composition cancomprise polymorph Form C and polymorph Form J. In other embodiments,the composition can comprise polymorph Form C and an amorphous form of acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or hydrate thereof. In one embodiment, the ratio of polymorph Form C tothe total amount of non-Form C polymorph(s) is greater than about 1:1,greater than about 2:1, greater than about 3:1, greater than about 4:1,greater than about 5:1, greater than about 6:1, greater than about 7:1,greater than about 8:1, or greater than about 9:1. In one embodiment,the composition comprising Form C is a pharmaceutical composition. Inone embodiment, the composition is at least about 98% by weight of acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or hydrate thereof.

In one embodiment, the composition comprises a mixture of polymorph FormA and at least one non-Form A polymorph of a compound of Formula (I), ora pharmaceutically acceptable salt, solvate, or hydrate thereof. Forexample, in certain embodiments, the composition can comprise polymorphForm A and polymorph Form B. In other embodiments, the composition cancomprise polymorph Form A and polymorph Form C. In other embodiments,the composition can comprise polymorph Form A and polymorph Form D. Inother embodiments, the composition can comprise polymorph Form A andpolymorph Form E. In other embodiments, the composition can comprisepolymorph Form A and polymorph Form F. In other embodiments, thecomposition can comprise polymorph Form A and polymorph Form G. In otherembodiments, the composition can comprise polymorph Form A and polymorphForm H. In other embodiments, the composition can comprise polymorphForm A and polymorph Form I. In other embodiments, the composition cancomprise polymorph Form A and polymorph Form J. In other embodiments,the composition can comprise polymorph Form A and an amorphous form of acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or hydrate thereof. In one embodiment, the ratio of polymorph Form A tothe total amount of non-Form A polymorph(s) is greater than about 1:1,greater than about 2:1, greater than about 3:1, greater than about 4:1,greater than about 5:1, greater than about 6:1, greater than about 7:1,greater than about 8:1, or greater than about 9:1. In one embodiment,the ratio of polymorph Form A to the total amount of non-Form Apolymorph(s) is less than about 1:1, less than about 2:1, less thanabout 3:1, less than about 4:1, less than about 5:1, less than about6:1, less than about 7:1, less than about 8:1, or less than about 9:1.In one embodiment, the composition comprising Form A is a pharmaceuticalcomposition. In one embodiment, the composition is at least about 98% byweight of a compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, or hydrate thereof.

In certain embodiments, provided herein is a composition comprising atherapeutically effective amount of a compound of Formula (I):

or a pharmaceutically acceptable salt, solvate, or hydrate thereof; andone or more pharmaceutically acceptable excipients.

In one embodiment, the composition comprises polymorph Form C of acompound of Formula (I). In one embodiment, the composition can furthercomprise one or more non-Form C polymorph(s) of a compound of Formula(I), or a pharmaceutically acceptable salt, solvate, or hydrate thereof.In certain embodiments, the ratio of polymorph Form C to the totalamount of non-Form C polymorph(s) is greater than about 1:1, greaterthan about 2:1, greater than about 3:1, greater than about 4:1, greaterthan about 5:1, greater than about 6:1, greater than about 7:1, greaterthan about 8:1, or greater than about 9:1. In one embodiment, thecomposition comprises polymorph Form A of a compound of Formula (I). Inone embodiment, the composition can further comprise one or morenon-Form A polymorph(s) of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or hydrate thereof. Incertain embodiments, the ratio of polymorph Form A to the total amountof non-Form A polymorph(s) is greater than about 1:1, greater than about2:1, greater than about 3:1, greater than about 4:1, greater than about5:1, greater than about 6:1, greater than about 7:1, greater than about8:1, or greater than about 9:1. In certain embodiments, the ratio ofpolymorph Form A to the total amount of non-Form A polymorph(s) is lessthan about 1:1, less than about 2:1, less than about 3:1, less thanabout 4:1, less than about 5:1, less than about 6:1, less than about7:1, less than about 8:1, or less than about 9:1.

In one embodiment, polymorph forms provided herein are useful in theproduction of medicinal preparations and can be obtained by means of acrystallization process to produce crystalline and semi-crystallineforms or a solidification process to obtain the amorphous form. Incertain embodiments, the crystallization is carried out by eithergenerating a compound of Formula (I) in a reaction mixture andrecovering a polymorph from the reaction mixture, or by dissolving acompound of Formula (I) in a solvent, optionally with heat, followed bycrystallizing/solidifying the product by cooling and/or by the additionof an anti-solvent for a period of time. The crystallization orsolidification can be followed by drying carried out under controlledconditions until a certain water content is reached in the endpolymorphic form.

In one embodiment, provided herein are methods of preparing one or morepolymorph(s) of a compound of the Formula (I):

or a pharmaceutically acceptable salt, solvate, or hydrate thereof.Polymorphs prepared according to a method provided herein include FormA, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, FormJ, or an amorphous form of a compound of Formula (I), or mixtures of twoor more thereof. In one embodiment, a polymorph provided herein is asolvate or hydrate of a compound of Formula (I). In one embodiment, apolymorph provided herein is a mono-acid or bis-acid addition salt, suchas, e.g., a mono-HCl salt or a bis-HCl salt of a compound of Formula(I), or a solvate or hydrate thereof.

In one embodiment, provided herein is a method of preparing a compoundof Formula (I):

or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

In one embodiment, the method comprises any one, two, three, four, five,six, seven, or eight, or more of the following steps:

wherein:

-   -   X is selected from fluoro, chloro, bromo, iodo.        —O—SO₂-4-methylphenyl, and —O—SO₂-methyl;    -   PG¹ is selected from benzyl, substituted benzyl,        methoxycarbonyl, ethoxycarbonyl, substituted ethoxycarbonyl,        9-fluorenyloxycarbonyl, substituted 9-fluorenyloxycarbonyl,        2,2,2,-trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl,        (2-phenyl-2-trimethylsilyl)ethoxycarbonyl,        2-phenylethoxycarbonyl, 1,1-dimethyl-2,2-dibromoethoxycarbonyl,        1,1-dimethyl-2,2,2-trichloroethoxycarbonyl, t-butoxycarbonyl,        1-adamantyloxycarbonyl, 2-adamantyloxycarbonyl,        triisopropylsiloxycarbonyl, vinyloxycarbonyl,        1-isopropoxycarbonyl, 8-quinolyloxycarbonyl,        2,4-dimethylpent-3-yloxycarbonyl, benzyloxycarbonyl, and        substituted benzyloxycarbonyl;    -   PG² is selected from methylsulfonyl, substituted methylsulfonyl,        benzenesulfonyl, substituted benzenesulfonyl, benzyloxycarbonyl,        substituted benzyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl,        2-trimethylsilylethoxycarbonyl, t-butoxycarbonyl,        1-adamantyloxycarbonyl, 2-adamantyloxycarbonyl, alkyl,        substituted alkyl, t-butyldimethylsilyl, triisopropylsilyl,        allyl, benzyl, substituted benzyl, hydroxymethyl, methoxymethyl,        diethoxymethyl. (2-chloroethoxy)methyl, t-butoxymethyl,        t-butyldimethylsiloxymethyl, pivaloyloxymethyl, benzyloxymethyl,        dimethylaminomethyl, 2-tetrahydropyranyl, substituted        alkoxymethyl and substituted aryloxymethyl; and    -   where substituents are selected from alkyl, heteroalkyl,        alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl,        heteroaryl, heteroarylalkyl, alkoxy, cycloalkoxy,        heterocyclyloxy, aryloxy, heteroaryloxy, amido, amino, acyl,        acyloxy, alkoxycarbonyl, ester, ether, thio, sulfinyl, sulfonyl,        sulfonamido, halo, cyano, hydroxyl, nitro, phosphate, urea,        carbamate, and carbonate.

In one embodiment, provided herein is a method of preparing a compoundof Formula (I), or a pharmaceutically acceptable salt, solvate, orhydrate thereof, comprising the following step:

wherein

-   -   PG¹ is selected from benzyl, substituted benzyl,        methoxycarbonyl, ethoxycarbonyl, substituted ethoxycarbonyl,        9-fluorenyloxycarbonyl, substituted 9-fluorenyloxycarbonyl,        2,2,2,-trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl,        (2-phenyl-2-trimethylsilyl)ethoxycarbonyl,        2-phenylethoxycarbonyl, 1,1-dimethyl-2,2-dibromoethoxycarbonyl,        1,1-dimethyl-2,2,2-trichloroethoxycarbonyl, t-butoxycarbonyl,        1-adamantyloxycarbonyl, 2-adamantyloxycarbonyl,        triisopropylsiloxycarbonyl, vinyloxycarbonyl.        I-isopropoxycarbonyl, 8-quinolyloxycarbonyl,        2,4-dimethylpent-3-yloxycarbonyl, benzyloxycarbonyl, and        substituted benzyloxycarbonyl; and    -   where substituents are selected from alkyl, heteroalkyl,        alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl,        heteroaryl, heteroarylalkyl, alkoxy, cycloalkoxy,        heterocyclyloxy, aryloxy, heteroaryloxy, amido, amino, acyl,        acyloxy, alkoxycarbonyl, ester, ether, thio, sulfinyl, sulfonyl,        sulfonamido, halo, cyano, hydroxyl, nitro, phosphate, urea,        carbamate, and carbonate.

In some embodiments. PG¹ is a carbamate protecting group, such as analkoxycarbonyl or aryloxycarbonyl. In one embodiment, PG¹ is selectedfrom t-butoxycarbonyl and benzyloxycarbonyl. In one embodiment, PG¹ ist-butoxycarbonyl.

In one embodiment, the step comprises combining the protected amino acidstarting material with N,O-dimethylhydroxylamine (e.g., as a free baseor in salt form such as an HCl salt) in the presence of an amidecoupling reagent to afford the amide product. In some embodiments, theamide coupling reagent can include, but is not limited to, EDCI, DCC,DIC. HATU, HBTU, HCTU, TBTU, and PyBOP, optionally in the presence ofHOBt. HOAt, and/or a base (e.g., an amine base such as Et₃N). In oneembodiment, the amide coupling reagent is EDCI in the presence of HOBt.

In one embodiment, provided herein is a method of preparing a compoundof Formula (I), or a pharmaceutically acceptable salt, solvate, orhydrate thereof, comprising the following step:

In one embodiment, the step comprises combining 2-chloro-6-methylbenzoicacid with, e.g., thionyl chloride or oxalyl chloride, optionally in thepresence of a catalytic amount of DMF, to afford2-chloro-6-methylbenzoyl chloride.

In one embodiment, provided herein is a method of preparing a compoundof Formula (I), or a pharmaceutically acceptable salt, solvate, orhydrate thereof, comprising the following step:

In one embodiment, the step comprises combining 2-chloro-6-methylbenzoylchloride with aniline to afford 2-chloro-6-methyl-N-phenylbenzamide. Inone embodiment, the step is optionally carried out in the presence of abase (e.g., an amine base such as Et₃N).

In one embodiment, provided herein is a method of preparing a compoundof Formula (I), or a pharmaceutically acceptable salt, solvate, orhydrate thereof, comprising the following step:

In one embodiment, the step comprises combining 2-chloro-6-methylbenzoicacid with aniline in the presence of an amide coupling reagent to afford2-chloro-6-methyl-N-phenylbenzamide. In some embodiments, the amidecoupling reagent can include, but is not limited to, EDCI, DCC, DIC,HATU, HBTU, HCTU, TBTU, and PyBOP, optionally in the presence of HOBt,HOAt. and/or a base (e.g., an amine base such as Et₃N). In certainembodiments, 2-chloro-6-methylbenzoic acid can be first converted to anacyl halide (e.g., using SOCl₂) or anhydride (e.g., using proceduresknown in the art such as, but not limited to, combining with one or moreequivalents of a suitable acid, such as alkyl-COOH, and a couplingreagent), and the acyl halide or anhydride is combined with aniline toafford 2-chloro-6-methyl-N-phenylbenzamide.

In one embodiment, provided herein is a method of preparing a compoundof Formula (I), or a pharmaceutically acceptable salt, solvate, orhydrate thereof, comprising the following step:

wherein

-   -   PG¹ is selected from benzyl, substituted benzyl,        methoxycarbonyl, ethoxycarbonyl, substituted ethoxycarbonyl,        9-fluorenyloxycarbonyl, substituted 9-fluorenyloxycarbonyl,        2,2,2,-trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl.        (2-phenyl-2-trimethylsilyl)ethoxycarbonyl,        2-phenylethoxycarbonyl, 1,1-dimethyl-2,2-dibromoethoxycarbonyl,        1,1-dimethyl-2,2,2-trichloroethoxycarbonyl, t-butoxycarbonyl,        1-adamantyloxycarbonyl, 2-adamantyloxycarbonyl,        triisopropylsiloxycarbonyl, vinyloxycarbonyl,        1-isopropoxycarbonyl, 8-quinolyloxycarbonyl,        2,4-dimethylpent-3-yloxycarbonyl, benzyloxycarbonyl, and        substituted benzyloxycarbonyl; and    -   where substituents are selected from alkyl, heteroalkyl,        alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl,        heteroaryl, heteroarylalkyl, alkoxy, cycloalkoxy,        heterocyclyloxy, aryloxy, heteroaryloxy, amido, amino, acyl,        acyloxy, alkoxycarbonyl, ester, ether, thio, sulfinyl, sulfonyl,        sulfonamido, halo, cyano, hydroxyl, nitro, phosphate, urea,        carbamate, and carbonate.

In some embodiments, PG¹ is a carbamate protecting group, such as analkoxycarbonyl or aryloxycarbonyl. In one embodiment, PG¹ is selectedfrom t-butoxycarbonyl and benzyloxycarbonyl. In one embodiment, PG¹ ist-butoxycarbonyl.

In one embodiment, the starting material of the step,2-chloro-6-methyl-N-phenylbenzamide, is combined with(S)-tert-butyl(I-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate inthe presence of an alkyllithium, such as n-butyllithium orn-hexyllithium, and to afford the protected amine. In anotherembodiment, 2-chloro-6-methyl-N-phenylbenzamide is combined withBoc-Ala-OMe. or other Ci, alkyl esters, under similar conditions toafford the protected amine. In another embodiment,(S)-tert-butyl(1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate iscombined with an alkyl Grignard reagent, such as, but not limited to,isopropyl Grignard (e.g., iPrMgCl), prior to addition to a mixturecomprising 2-chloro-6-methyl-N-phenylbenzamide. Other suitable Grignardreagents include, but are not limited to, organicmagnesium halides suchas organomagesium chlorides and organomagnesium bromides. Non-limitingexamples of Grignard reagents include methylmagnesium (chloride orbromide), substituted methylmagensium (chlorides or bromides) such as2-naphthylenylmethylmagensium (chloride or bromide),cyclohexylmethylmagensium (chloride or bromide), and 1,3-dioxanylmethylmagnesium (chloride or bromide), ethyl magnesium (chloride or bromide),phenylmagnesium (chloride or bromide), substituted phenylmagnesium(chlorides or bromides), and others known in the art.

In one embodiment, provided herein is a method of preparing a compoundof Formula (I), or a pharmaceutically acceptable salt, solvate, orhydrate thereof, comprising the following step:

wherein

-   -   PG¹ is selected from benzyl, substituted benzyl,        methoxycarbonyl, ethoxycarbonyl, substituted ethoxycarbonyl,        9-fluorenyloxycarbonyl, substituted 9-fluorenyloxycarbonyl,        2,2,2,-trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl,        (2-phenyl-2-trimethylsilyl)ethoxycarbonyl,        2-phenylethoxycarbonyl, 1,1-dimethyl-2,2-dibromoethoxycarbonyl,        1,1-dimethyl-2,2,2-trichloroethoxycarbonyl, t-butoxycarbonyl,        1-adamantyloxycarbonyl, 2-adamantyloxycarbonyl,        triisopropylsiloxycarbonyl, vinyloxycarbonyl.        I-isopropoxycarbonyl, 8-quinolyloxycarbonyl,        2,4-dimethylpent-3-yloxycarbonyl, benzyloxycarbonyl, and        substituted benzyloxycarbonyl; and    -   where substituents are selected from alkyl, heteroalkyl,        alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl,        heteroaryl, heteroarylalkyl, alkoxy, cycloalkoxy,        heterocyclyloxy, aryloxy, heteroaryloxy, amido, amino, acyl,        acyloxy, alkoxycarbonyl, ester, ether, thio, sulfinyl, sulfonyl,        sulfonamido, halo, cyano, hydroxyl, nitro, phosphate, urea,        carbamate, and carbonate.

In some embodiments, PG¹ is a carbamate protecting group, such as analkoxycarbonyl or aryloxycarbonyl. In one embodiment, PG¹ is selectedfrom t-butoxycarbonyl and benzyloxycarbonyl. In one embodiment, PG¹ ist-butoxycarbonyl.

In one embodiment, the protected amine is combined with an inorganicacid, such as HCl or trifluoroacetic acid, to afford the isoquinolinone.Other suitable acids include, but are not limited to, methanesulfonicacid, sulfuric acid, hydrobromic acid, nitric acid, phosphoric acid,perchloric acid, and camphorsulfonic acid.

In one embodiment, provided herein is a method of preparing a compoundof Formula (I), or a pharmaceutically acceptable salt, solvate, orhydrate thereof, comprising the following step:

wherein

-   -   X is selected from fluoro, chloro, bromo, iodo.        —O—SO₂-4-methylphenyl, and —O—SO₂-methyl;    -   PG² is selected from methylsulfonyl, substituted methylsulfonyl,        benzenesulfonyl, substituted benzenesulfonyl, benzyloxycarbonyl,        substituted benzyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl,        2-trimethylsilylethoxycarbonyl, t-butoxycarbonyl,        1-adamantyloxycarbonyl, 2-adamantyloxycarbonyl, alkyl,        substituted alkyl, t-butyldimethylsilyl, triisopropylsilyl,        allyl, benzyl, substituted benzyl, hydroxymethyl, methoxymethyl,        diethoxymethyl. (2-chloroethoxy)methyl, t-butoxymethyl,        t-butyldimethylsiloxymethyl, pivaloyloxymethyl, benzyloxymethyl,        dimethylaminomethyl, 2-tetrahydropyranyl, substituted        alkoxymethyl and substituted aryloxymethyl, and    -   where substituents are selected from alkyl, heteroalkyl,        alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl,        heteroaryl, heteroarylalkyl, alkoxy, cycloalkoxy,        heterocyclyloxy, aryloxy, heteroaryloxy, amido, amino, acyl,        acyloxy, alkoxycarbonyl, ester, ether, thio, sulfinyl, sulfonyl,        sulfonamido, halo, cyano, hydroxyl, nitro, phosphate, urea,        carbamate, and carbonate.

In one embodiment. PG² is 2-tetrahydropyranyl. In some embodiments, X isselected from fluoro, chloro, bromo, and iodo. In one embodiment, X ischloro. In certain embodiments, the step comprises combining6-chloro-9H-purine with 3,4-dihydro-2H-pyran to afford6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine.

In one embodiment, provided herein is a method of preparing a compoundof Formula (I), or a pharmaceutically acceptable salt, solvate, orhydrate thereof, comprising the following step:

wherein

-   -   X is selected from fluoro, chloro, bromo, iodo,        —O—SO₂-4-methylphenyl, and —O—SO₂-methyl.    -   PG² is selected from methylsulfonyl, substituted methylsulfonyl,        benzenesulfonyl, substituted benzenesulfonyl, benzyloxycarbonyl,        substituted benzyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl,        2-trimethylsilylethoxycarbonyl, t-butoxycarbonyl,        1-adamantyloxycarbonyl, 2-adamantyloxycarbonyl, alkyl,        substituted alkyl, t-butyldimethylsilyl, triisopropylsilyl,        allyl, benzyl, substituted benzyl, hydroxymethyl, methoxymethyl,        diethoxymethyl. (2-chloroethoxy)methyl, t-butoxymethyl,        t-butyldimethylsiloxymethyl, pivaloyloxymethyl, benzyloxymethyl,        dimethylaminomethyl, 2-tetrahydropyranyl, substituted        alkoxymethyl and substituted aryloxymethyl, and    -   where substituents are selected from alkyl, heteroalkyl,        alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl,        heteroaryl, heteroarylalkyl, alkoxy, cycloalkoxy,        heterocyclyloxy, aryloxy, heteroaryloxy, amido, amino, acyl,        acyloxy, alkoxycarbonyl, ester, ether, thio, sulfinyl, sulfonyl,        sulfonamido, halo, cyano, hydroxyl, nitro, phosphate, urea,        carbamate, and carbonate.

In one embodiment, PG² is 2-tetrahydropyranyl. In some embodiments. X isselected from fluoro, chloro, bromo, and iodo. In one embodiment, X ischloro. In one embodiment, the protected chloropurine is combined withthe isoquinolinone in the presence of a base, such as an amine base(e.g., Et₂N), in an alcoholic solvent (e.g., McOH, EtOH. PrOH, iPrOH).

In one embodiment, provided herein is a method of preparing a compoundof Formula (I), or a pharmaceutically acceptable salt, solvate, orhydrate thereof, comprising the following step:

wherein

-   -   PG² is selected from methylsulfonyl, substituted methylsulfonyl,        benzenesulfonyl, substituted benzenesulfonyl, benzyloxycarbonyl,        substituted benzyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl,        2-trimethylsilylethoxycarbonyl, t-butoxycarbonyl,        1-adamantyloxycarbonyl, 2-adamantyloxycarbonyl, alkyl,        substituted alkyl, t-butyldimethylsilyl, triisopropylsilyl,        allyl, benzyl, substituted benzyl, hydroxymethyl, methoxymethyl,        diethoxymethyl, (2-chloroethoxy)methyl, t-butoxymethyl,        t-butyldimethylsiloxymethyl, pivaloyloxymethyl, benzyloxymethyl,        dimethylaminomethyl, 2-tetrahydropyranyl, substituted        alkoxymethyl and substituted aryloxymethyl, and    -   where substituents are selected from alkyl, heteroalkyl,        alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl,        heteroaryl, heteroarylalkyl, alkoxy, cycloalkoxy,        heterocyclyloxy, aryloxy, heteroaryloxy, amido, amino, acyl,        acyloxy, alkoxycarbonyl, ester, ether, thio, sulfinyl, sulfonyl,        sulfonamido, halo, cyano, hydroxyl, nitro, phosphate, urea,        carbamate, and carbonate.

In one embodiment, PG² is 2-tetrahydropyranyl. In one embodiment, theprotected purine is combined with an inorganic acid, such as, but notlimited to, HCl, HBr, perchloric acid, sulfuric acid, nitric acid, andphosphoric acid, in an alcoholic solvent (e.g., MeOH, EtOH, PrOH,iPrOH). In one embodiment, the inorganic acid is HCl.

In one embodiment, provided herein is a method of preparing a compoundof Formula (I), or a pharmaceutically acceptable salt, solvate, orhydrate thereof, comprising the following step:

-   -   X is selected from fluoro, chloro, bromo, iodo,        —O—SO₂-4-methylphenyl, and —O—SO₂-methyl.

In some embodiments, X is selected from fluoro, chloro, bromo, and iodo.In one embodiment, X is chloro. In one embodiment, the startingmaterials are combined with an amine base, such as Et₃N, in an alcoholicsolvent, such as glycerol, to effect amine coupling.

In some embodiments, the intermediates for the synthesis of a compoundof Formula (I), or a salt, solvate, or hydrate thereof, are madeaccording to one or more of the following schemes.

In one embodiment, the conversion of compound 1 to compound 2 can beperformed according to any method in the art. In one embodiment,compound 1 is combined with MeNHOMe (HCl) in the presence of EDCI andHOBt. In certain embodiments, a base such as triethylamine can bepresent.

In one embodiment, the conversion of compound 3 to compound 4 occurs inthe presence of para-toluenesulfonic acid. In another embodiment,installation of the THP protecting group occurs using camphorsulphonicacid in 2-methyltetrahydrofuran.

In one embodiment, the conversion of compound 5 to compound 7 can beperformed according to any method in the art. In one embodiment,compound 5 is combined with thionyl chloride and DMF to yield compound6, which is in turn combined with aniline to afford compound 7.

In one embodiment, compound 7 is converted to compound 8 by combiningcompound 7 with n-hexyl lithium and then adding compound 2, which hasbeen previously combined with isopropyl Grignard (e.g., iPrMgCl). In oneembodiment, compound 8 is converted to compound 9 in the presence ofacid, such as hydrochloric acid, trifluoroacetic acid, ormethanesulfonic acid, in a solvent, such as methanol or isopropylalcohol. In one embodiment, the acid can be trifluoroacetic acid.

In one embodiment, a compound of Formula (I), or a salt, solvate, orhydrate thereof, is prepared by combining compound 3 and compound 9according to the following scheme:

In one embodiment, the starting materials 3 and 9 are combined with anamine base, such as Et₃N, in an alcoholic solvent, such as glycerol, toeffect purine coupling.

In one embodiment, the following synthetic scheme can be followed toprepare a compound of Formula (I), or a salt, solvate, or hydratethereof:

wherein

-   -   PG² is selected from methylsulfonyl, substituted methylsulfonyl,        benzenesulfonyl, substituted benzenesulfonyl, benzyloxycarbonyl,        substituted benzyloxycarbonyl, 2.2.2,-trichloroethoxycarbonyl,        2-trimethylsilylethoxycarbonyl, t-butoxycarbonyl,        1-adamantyloxycarbonyl, 2-adamantyloxycarbonyl, alkyl,        substituted alkyl, t-butyldimethylsilyl, triisopropylsilyl,        allyl, benzyl, substituted benzyl, hydroxymethyl, methoxymethyl,        diethoxymethyl, (2-chloroethoxy)methyl, t-butoxymethyl,        t-butyldimethylsiloxymethyl, pivaloyloxymethyl, benzyloxymethyl,        dimethylaminomethyl, 2-tetrahydropyranyl, substituted        alkoxymethyl and substituted aryloxymethyl, and    -   where substituents are selected from alkyl, heteroalkyl,        alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl,        heteroaryl, heteroarylalkyl, alkoxy, cycloalkoxy,        heterocyclyloxy, aryloxy, heteroaryloxy, amido, amino, acyl,        acyloxy, alkoxycarbonyl, ester, ether, thio, sulfinyl, sulfonyl,        sulfonamido, halo, cyano, hydroxyl, nitro, phosphate, urea,        carbamate, and carbonate.

While shown above in two steps, the above synthetic scheme can becarried out as a one-pot reaction. In one embodiment, the first step toafford compound (Ia) can be carried out in the presence of base (e.g.,an amine base such as, but not limited to. Et₃N) in an alcoholic solvent(e.g., MeOH. EtOH, PrOH, iPrOH). Depending on the nature of the PG²protecting group, the following reagents can be used to deprotectcompound (Ia) to afford compound (I). One or more reagents to remove theprotecting group PG² includes, but is not limited to, acids such as HCl.HBr and TFA; carbonate bases, such as Na₂CO₃ and K₂CO₃; hydroxide bases,such as NaOH and KOH; lithium bases, such as methyl lithium, ethyllithium, propyl lithium, n-butyl lithium, n-pentyl lithium, and n-hexyllithium; oxidants such as ceric ammonium nitrate; hydrogenationconditions, such as cyclohexadiene/Pd black, and H₂/Pd on carbon; TBAF,and BF₃.Et₂O.

In one embodiment, the following synthetic scheme is used to prepare acompound of Formula (I), or a salt, solvate, or hydrate thereof:

In one embodiment, the first step to afford compound 10 can be carriedout in the presence of base (e.g., an amine base such as, but notlimited to, Et₃N) in an alcoholic solvent (e.g., MeOH. EtOH, PrOH,iPrOH). In certain embodiments, a compound of Formula (I), or a salt,solvate, or hydrate thereof, is obtained from treatment of a protectedprecursor (e.g., compound 10) with hydrochloric acid in ethanol followedby treatment with dichloromethane. In certain embodiments, the productfrom treatment with dichloromethane is treated under aqueous conditions,such as about 90% water and about 10% 2-propanol.

In one embodiment, recovery and purification of the chemical entitiesand intermediates described herein can be effected by procedures, suchas, but not limited to, filtration, extraction, crystallization,precipitation, silica gel column chromatography, high pressure liquidchromatography, thin-layer chromatography or thick-layer chromatography,or a combination of these procedures. Non-limiting exemplaryillustrations of suitable recovery and purification procedures areprovided in the examples below. However, other recovery and purificationprocedures known in the art can also be used.

Prior to formulation as the active pharmaceutical ingredient in a drugproduct, a compound of Formula (I), or a salt, solvate, or hydratethereof, can be isolated in greater than about 90% purity, greater thanabout 91% purity, greater than about 92% purity, greater than about 93%purity, greater than about 94% purity, greater than about 95% purity,greater than about 96% purity, greater than about 97% purity, greaterthan about 98% purity, greater than about 99% purity, and purityapproaching 100/c.

In some embodiments, the (R)- and (S)-isomers of a compound of Formula(I), if both present, can be resolved by methods known to those skilledin the art, for example by formation of diastereoisomeric salts orcomplexes which can be separated, for example, by crystallization; viaformation of diastereoisomeric derivatives which can be separated, forexample, by crystallization, gas-liquid or liquid chromatography;selective reaction of one enantiomer with an enantiomer-specificreagent, for example enzymatic oxidation or reduction, followed byseparation of the modified and unmodified enantiomers; or gas-liquid orliquid chromatography in a chiral environment, for example on a chiralsupport, such as silica with a bound chiral ligand or in the presence ofa chiral solvent. Alternatively, a certain enantiomer can be synthesizedby asymmetric synthesis using optically active reagents, substrates,catalysts or solvents, or by converting one enantiomer to the other byasymmetric transformation. In certain embodiments, a compound of Formula(I) is present as a racemic or non-racemic mixture with its enantiomer.In one embodiment, a compound of Formula (I) is present in enantiomericexcess (cc) selected from greater than about 60%, greater than about65%, greater than about 70%, greater than about 75%, greater than about80/6, greater than about 85%, greater than about 90%, greater than about910%, greater than about 92%, greater than about 93%, greater than about94%, greater than about 95%, greater than about 96/6, greater than about97%, greater than about 98%, and greater than about 99%.

In one embodiment, provided herein is a method of preparing a polymorphof a compound of Formula (I):

or a pharmaceutically acceptable salt, solvate, or hydrate thereof. Inone embodiment, the method comprises recovering a polymorph as a firstsolid form after synthesis of a compound of Formula (I). In anotherembodiment, the method comprises recovering a polymorph as a transitionfrom a prior solid form of a compound of Formula (I) (e.g., firstrecovering a solid form of a first polymorph of a compound of Formula(I), or a salt, solvate, or hydrate thereof, and converting therecovered solid form to a second polymorph under suitable conditions).Transitions from one polymorphic form to another am within the scope ofthe disclosure. In one embodiment, such transition processes can be usedas a manufacturing method for obtaining a form for the production ofmedicinal preparations.

In one embodiment, provided herein is a method of preparing polymorphForm C of a compound of Formula (I):

wherein the method comprises:

-   -   (i) combining a compound of Formula (Ia):

wherein

-   -   PG² is a protecting group selected from methylsulfonyl,        substituted methylsulfonyl, benzenesulfonyl, substituted        benzenesulfonyl, benzyloxycarbonyl, substituted        benzyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl,        2-trimethylsilylethoxycarbonyl, t-butoxycarbonyl,        1-adamantyloxycarbonyl, 2-adamantyloxycarbonyl, alkyl,        substituted alkyl, t-butyldimethylsilyl, triisopropylsilyl,        allyl, benzyl, substituted benzyl, hydroxymethyl, methoxymethyl,        diethoxymethyl, (2-chloroethoxy)methyl, t-butoxymethyl,        t-butyldimethylsiloxymethyl, pivaloyloxymethyl, benzyloxymethyl,        dimethylaminomethyl, 2-tetrahydropyranyl, substituted        alkoxymethyl and substituted aryloxymethyl, and    -   where substituents are selected from alkyl, heteroalkyl,        alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl,        heteroaryl, heteroarylalkyl, alkoxy, cycloalkoxy,        heterocyclyloxy, aryloxy, heteroaryloxy, amido, amino, acyl,        acyloxy, alkoxycarbonyl, ester, ether, thio, sulfinyl, sulfonyl,        sulfonamido, halo, cyano, hydroxyl, nitro, phosphate, urea,        carbamate, and carbonate; with one or more reagents to remove        the protecting group PG² to form a compound of Formula (I);        and (ii) recovering polymorph Form C of the compound of Formula        (I); wherein at least one of steps (i) and (ii) occurs in a        non-anhydrous condition.

In some embodiments, one or more reagents to remove the protecting groupPG² includes, but is not limited to, acids such as HCl. HBr and TFA;carbonate bases, such as Na₂CO₃ and K₂CO₃; hydroxide bases, such as NaOHand KOH; lithium bases, such as methyl lithium, ethyl lithium, propyllithium, n-butyl lithium, n-pentyl lithium, and n-hexyl lithium;oxidants such as ceric ammonium nitrate; hydrogenation conditions, suchas cyclohexadiene/Pd black, and H₂/Pd on carbon; TBAF, and BF₃.Et₂O. Inone embodiment, a non-anhydrous condition includes water, such as in aform of water vapor and/or liquid water. In one embodiment, anon-anhydrous condition includes a solvent system comprising a non-watersolvent and liquid water, as described herein elsewhere.

In one embodiment, provided herein is a method of preparing a polymorphForm C of a compound of Formula (I):

wherein the method comprises:

-   -   (i) exposing a composition comprising at least one non-Form C        polymorph of a compound of Formula (I), or a salt, solvate, or        hydrate thereof, to a non-anhydrous condition for a period of        time sufficient to convert at least about 50% of the total        amount of non-Form C polymorph(s) into Form C of a compound of        Formula (I); and    -   (ii) recovering said polymorph Form C.

In certain embodiments, the recovering step involves recrystallizationof the reaction product from a mono-solvent system. In certainembodiments, the recovering step involves recrystallization of theproduct from a binary, tertiary, or greater solvent system, wherebinary, tertiary, or greater solvent systems are collectively understoodas multi-solvent systems. In certain embodiments, the recovering stepinvolves crystallization from a mono- or multi-solvent system, where thecrystallization involves cooling a solution containing a compound ofFormula (I). In certain embodiments, the recovering step involvescrystallization from a mono- or multi-solvent system, where thecrystallization involves addition of an anti-solvent either with orwithout a cooling step to cause precipitation of Form C. In certainembodiments, the conditions of crystallization are non-anhydrous. Wherethe conditions are non-anhydrous, water can be present in trace amounts,or in amounts less than about 1% by volume of solvent, or present aswater vapor. In certain embodiments, water can be present as aco-solvent (or anti-solvent), for example, in an amount between about 1%and about 50%. For example, water can be present in about 5/a, about10%, about 15%, about 20/a, about 25%, about 30%, about 35%, about 40%,about 45%, and about 50% by volume of solvent. In certain embodiments,water can be present in amounts equal to or greater than about 50% byvolume of solvent. For example, water can be present in about 55%, about60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%,about 95%, and up to 100% by volume of solvent. In certain embodiments,liquid water is present in a multi-solvent system, for example, in anamount between about 10% to about 50% by volume of the solvent system.In certain embodiments, liquid water is present in a multi-solventsystem, in an amount equal to or greater than about 50% by volume of thesolvent system. In certain embodiments, water can be present as watervapor or ambient humidity.

In one embodiment, the non-water solvent is a water-miscible solvent.For example, liquid water can be present in an amount of about 1%, about2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about9%, about 10%, about 15%, about 20%, about 250/a, about 30%, about 35%,about 40/a, about 45%, about 50%, about 55%, about 60%, about 650/a,about 70%, about 75%, about 80/a, about 85%, about 90%, about 95%, about96%, about 97%, about 98%, about 99%, or about 100% by volume of thesolvent system. In one embodiment, liquid water is present in an amountof between about 10% and about 50% by volume of the solvent system.

In one embodiment, a non-anhydrous condition includes a solvent systemcomprising water (e.g., about 90% v/v) and isopropyl alcohol (e.g.,about 10% v/v). In one embodiment, a non-anhydrous condition includes asolvent system comprising water and ethanol. In one embodiment, anon-anhydrous condition includes a solvent system comprising water and awater-miscible solvent, such as, e.g., C₁-C₄ alcohol, acetone,acetonitrile, among others. In one embodiment, a water-miscible solventis an alcohol, such as, e.g., methanol, ethanol, 1-propanol, 2-propanol,1-butanol, 2-butanol, t-butanol, ethylene glycol, among others. In oneembodiment, the ratio of water and water-miscible solvent in a solventsystem provided herein is about 50:1, about 40:1, about 30:1, about20:1, about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1,about 4:1, about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10,about 1:20, about 1:30, about 1:40, or about 1:50 v/v. In oneembodiment, the ratio of water and water-miscible solvent in a solventsystem provided herein is from about 50:1 to about 1:1, from about 40:1to about 1:1, from about 30:1 to about 1:1, from about 20:1 to about1:1, from about 10:1 to about 1:1, from about 9:1 to about 1:1, fromabout 8:1 to about 1:1, from about 7:1 to about 1:1, from about 6:1 toabout 1:1, from about 5:1 to about 1:1, from about 4:1 to about 1:1,from about 3:1 to about 3:1, from about 2:1 to about 1:2, from about 1:1to about 1:4, from about 1:1 to about 1:5, from about 1:1 to about 1:6,from about 1:1 to about 1:7, from about 1:1 to about 1:8, from about 1:1to about 1:9, from about 1:1 to about 1:10, from about 1:1 to about1:20, from about 1:1 to about 1:30, from about 1:1 to about 1:40, orfrom about 1:1 to about 1:50 v/v.

In one embodiment, provided herein is a method of preparing polymorphForm A of a compound of Formula (I):

wherein the method comprises

-   -   (i) combining a compound of Formula (Ia):

wherein

-   -   PG² is a protecting group selected from methylsulfonyl,        substituted methylsulfonyl, benzenesulfonyl, substituted        benzenesulfonyl, benzyloxycarbonyl, substituted        benzyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl,        2-trimethylsilylethoxycarbonyl, t-butoxycarbonyl,        1-adamantyloxycarbonyl, 2-adamantyloxycarbonyl, alkyl,        substituted alkyl, t-butyldimethylsilyl, triisopropylsilyl,        allyl, benzyl, substituted benzyl, hydroxymethyl, methoxymethyl,        diethoxymethyl. (2-chloroethoxy)methyl, t-butoxymethyl,        t-butyldimethylsiloxymethyl, pivaloyloxymethyl, benzyloxymethyl,        dimethylaminomethyl, 2-tetrahydropyranyl, substituted        alkoxymethyl and substituted aryloxymethyl, and    -   where substituents are selected from alkyl, heteroalkyl,        alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl,        heteroaryl, heteroarylalkyl, alkoxy, cycloalkoxy,        heterocyclyloxy, aryloxy, heteroaryloxy, amido, amino, acyl,        acyloxy, alkoxycarbonyl, ester, ether, thio, sulfinyl, sulfonyl,        sulfonamido, halo, cyano, hydroxyl, nitro, phosphate, urea,        carbamate, and carbonate; with one or more reagents to remove        the protecting group PG² to form a compound of Formula (I); and    -   (ii) recovering polymorph Form A of the compound of Formula (I).

In some embodiments, one or more reagents to remove the protecting groupPG² includes, but is not limited to, acids such as HCl. HBr and TFA;carbonate bases, such as Na₂CO₃ and K₂CO₃; hydroxide bases, such as NaOHand KOH; lithium bases, such as methyl lithium, ethyl lithium, propyllithium, n-butyl lithium, n-pentyl lithium, and n-hexyl lithium:oxidants such as ceric ammonium nitrate; hydrogenation conditions, suchas cyclohexadiene/Pd black, and H₂/Pd on carbon; TBAF, and BF₃-Et₂O.

In some embodiments, step (ii) can include recrystallization of acompound of Formula (I), or a salt, solvate, or hydrate thereof, from amono-solvent system, or from a multi-solvent system that does notcontain both ethyl acetate and hexane. In certain embodiments, themethod further comprises a step of dissolving a compound of Formula (I),or a salt, solvate, or hydrate thereof, in a mono-solvent system or amulti-solvent system, removing residual solid matter to yield a liquidsolution, cooling said liquid solution at a rate to effectcrystallization of Form A, and recovering Form A from the liquidsolution.

In certain embodiments, the recovered polymorph is Form A. and therecovery step involves recrystallization of a reaction product from amono-solvent system. In certain embodiments, the recovered polymorph isForm A, and the recovering step involves recrystallization of theproduct from a binary, tertiary, or greater solvent system, collectivelyunderstood as a multi-solvent system, where the multi-solvent systemdoes not contain both ethyl acetate and hexane. In certain embodiments,the recovered polymorph is Form A, and the recovering step involvescrystallization from a mono- or multi-solvent system, where thecrystallization involves cooling a solution containing a compound ofFormula (I). In certain embodiments, the recovered polymorph is Form A.and the recovery step involves crystallization from a mono- ormulti-solvent system, where the crystallization involves addition of ananti-solvent either with or without a cooling step to enable recovery ofForm A.

In one embodiment, provided herein is a method of preparing polymorphForm B of a compound of Formula (I):

the method comprising thermal conversion from a non-Form B polymorph ofa compound of Formula (I), or a salt, solvate, or hydrate thereof, toyield polymorph Form B.

In certain embodiments, a non-Form B polymorph is a solid form of acompound of Formula (I), or a salt, solvate, or hydrate thereof (e.g., acrystalline form, an amorphous form, or a mixture of crystalline form(s)and/or amorphous form(s)), which is not polymorph Form B of a compoundof Formula (I). In one embodiment, a non-Form B polymorph is Form A,Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, or anamorphous form of a compound of Formula (I), or a salt, solvate, orhydrate thereof, or a mixture of two or more thereof.

In certain embodiments, provided herein are methods of preparing apolymorph of a compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, or hydrate thereof, wherein the method comprisesconverting a first polymorph or a mixture of polymorphs of a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, or hydratethereof, into a second polymorph of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or hydrate thereof. Incertain embodiments, the methods comprise exposing a compositioncomprising one or more polymorphs to conditions sufficient to convert atleast about 50% of the total amount of an original polymorph or a firstpolymorph into a second polymorph, and optionally recovering the secondpolymorph.

In certain embodiments, an original solid form or a first solid form ofa compound of Formula (I), or a pharmaceutically acceptable salt,solvate, or hydrate thereof, contains greater than about 50% non-Form Apolymorph(s) as the first polymorph, and the second polymorph is Form A.

In certain embodiments, the original solid form or a first solid form ofa compound of Formula (I), or a pharmaceutically acceptable salt,solvate, or hydrate thereof, contains greater than about 50% non-Form Cpolymorph(s), and the second polymorph is Form C. In one embodiment, theconversion to Form C is performed in a non-anhydrous condition for aperiod of time sufficient to convert at least about 50% of the totalamount of non-Form C polymorph(s) into Form C of a compound of Formula(I), with an optional step of recovering Form C from any non-Form Cpolymorph(s). Non-anhydrous conditions can include exposure of theoriginal solid form or composition to water vapor or to liquid water.For example, non-anhydrous conditions can include exposure of theoriginal solid form or composition to an amount of liquid water, eitheralone or with additional liquids or other components, to form a slurry.In certain embodiments, the original solid form or composition can beexposed to water vapor or humidity conditions for a time and at atemperature sufficient to effect conversion to Form C. In certainembodiments, the original composition comprises one or more of Form A,Form B, Form D, Form E, Form F, Form G, Form H, Form I, Form J. or anamorphous form of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or hydrate thereof, or a mixture of two ormore thereof. In certain embodiments, the original composition comprisesgreater than about 50% by weight polymorph Form A.

In certain embodiments, provided herein are compositions comprising apolymorph of a compound of Formula (I). In some embodiments, thepolymorph of a compound of Formula (I) is a pharmaceutically acceptablesalt, solvate, or hydrate. In certain embodiments, the compositioncomprises a mixture of a first polymorph of a compound of Formula (I),and one or more additional forms of a compound of Formula (I), e.g., anamorphous form of a compound of Formula (I), and/or one or moredifferent polymorphs of a compound of Formula (I). In such a mixture,the first polymorph, the amorphous form, and the one or more differentpolymorphs can each independently be in the form of a pharmaceuticallyacceptable salt, solvate or hydrate thereof as disclosed herein, and notwo salts, solvates or hydrates are necessarily the same as another ordifferent than another.

In some embodiments, the composition comprises a mixture of forms of acompound of Formula (I) as disclosed herein, and has a greater amount ofa first polymorph of a compound of Formula (I) relative to one or moreadditional forms of a compound of Formula (I) in the mixture. In certainembodiments, the first polymorph of a compound of Formula (I) isselected from Form A, Form B, Form C, Form D, Form E, Form F, Form G,Form H, Form I, and Form J. In some embodiments, the one or moreadditional forms of a compound of Formula (I) are selected from one ormore polymorphs of a compound of Formula (I) that are not the samepolymorph as the first polymorph, and an amorphous form of a compound ofFormula (I). In such a mixture, the first polymorph, the amorphous form,and the one or more different polymorphs can each independently be inthe form of a pharmaceutically acceptable salt, solvate or hydratethereof as disclosed herein, and no two salts, solvates or hydrates arenecessarily the same as another or different than another.

In some embodiments, the composition comprises a weight ratio of greaterthan about 1:1, greater than about 2:1, greater than about 3:1, greaterthan about 4:1, greater than about 5:1, greater than about 6:1, greaterthan about 7:1, greater than about 8:1, greater than about 9:1, greaterthan about 10:1, greater than about 20:1, greater than about 30:1,greater than about 40:1, greater than about 50:1, greater than about60:1, greater than about 70:1, greater than about 80:1, greater thanabout 90:1, or greater than about 99:1 of a first polymorph (e.g., FormA, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, orForm J) relative to the one or more additional forms of a compound ofFormula (I).

For example, in certain embodiments, the composition comprises Form C tonon-Form C polymorph(s) at a weight ratio of greater than about 1:1,greater than about 2:1, greater than about 3:1, greater than about 4:1,greater than about 5:1, greater than about 6:1, greater than about 7:1,greater than about 8:1, greater than about 9:1, greater than about 10:1,greater than about 20:1, greater than about 30:1, greater than about40:1, greater than about 50:1, greater than about 60:1, greater thanabout 70:1, greater than about 80:1, greater than about 90:1, or greaterthan about 99:1. In certain embodiments, the composition comprises afirst polymorph of a compound of Formula (I), e.g., Form C, and issubstantially free of other forms of the compound of Formula (I). Incertain embodiments, the composition comprises Form C and Form A. Incertain embodiments, the composition comprises Form C and Form B. Incertain embodiments, the composition comprises Form C and Form D. Incertain embodiments, the composition comprises Form C and Form E. Incertain embodiments, the composition comprises Form C and Form F. Incertain embodiments, the composition comprises Form C and Form G. Incertain embodiments, the composition comprises Form C and Form H. Incertain embodiments, the composition comprises Form C and Form I. Incertain embodiments, the composition comprises Form C and Form J. Incertain embodiments, the composition comprises Form C and an amorphousform of a compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, or hydrate thereof.

In certain embodiments, provided herein is a composition comprising FormA and one or more non-Form A polymorphs of a compound of Formula (I), orone or more pharmaceutically acceptable salts, solvates, or hydratesthereof. In certain embodiments, provided herein is a compositioncomprising Form B and one or more non-Form B polymorphs of a compound ofFormula (I), or one or more pharmaceutically acceptable salts, solvates,or hydrates thereof. In certain embodiments, provided herein is acomposition comprising Form C and one or more non-Form C polymorphs of acompound of Formula (I), or one or more pharmaceutically acceptablesalts, solvates, or hydrates thereof. In certain embodiments, providedherein is a composition comprising Form D and one or more non-Form Dpolymorphs of a compound of Formula (I), or one or more pharmaceuticallyacceptable salts, solvates, or hydrates thereof. In certain embodiments,provided herein is a composition comprising Form E and one or morenon-Form E polymorphs of a compound of Formula (I), or one or morepharmaceutically acceptable salts, solvates, or hydrates thereof. Incertain embodiments, provided herein is a composition comprising Form Fand one or more non-Form F polymorphs of a compound of Formula (I), orone or more pharmaceutically acceptable salts, solvates, or hydratesthereof. In certain embodiments, provided herein is a compositioncomprising Form G and one or more non-Form G polymorphs of a compound ofFormula (I), or one or more pharmaceutically acceptable salts, solvates,or hydrates thereof. In certain embodiments, provided herein is acomposition comprising Form H and one or more non-Form H polymorphs of acompound of Formula (I), or one or more pharmaceutically acceptablesalts, solvates, or hydrates thereof. In certain embodiments, providedherein is a composition comprising Form I and one or more non-Form Ipolymorphs of a compound of Formula (I), or one or more pharmaceuticallyacceptable salts, solvates, or hydrates thereof. In certain embodiments,provided herein is a composition comprising Form J and one or morenon-Form J polymorphs of a compound of Formula (I), or one or morepharmaceutically acceptable salts, solvates, or hydrates thereof. Incertain embodiments, provided herein is a composition comprising anamorphous form of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or hydrate thereof. In certain embodiments,provided herein is a composition comprising an amorphous form of acompound of Formula (I) and one or more polymorphs of a compound ofFormula (I) selected from Form A, B, C, D, E, F, G, H, I, and J, or oneor more pharmaceutically acceptable salts, solvates, or hydratesthereof. In certain embodiments, provided herein arm compositionscomprising one or more of Form A, B, C, D, E, F, G, H, I, J, oramorphous form, or one or more pharmaceutically acceptable salts,solvates, or hydrates thereof.

In some embodiments, a polymorphic Form of a compound of Formula (I) canbe obtained by dissolving a starting compound of Formula (I) (e.g., adifferent polymorphic Form, an amorphous form, or a salt, solvate, orhydrate thereof, of any of these chemical entities) in a solvent. Insome embodiments, the solvent can be a minimal amount required todissolve the starting compound of Formula (I) at either room temperatureor an elevated temperature. Optionally, the solution can be filtered. Insome instances, an anti-solvent (e.g., a solvent that the startingcompound is less soluble in than the first solvent) can be added to thesolution. In the case of an elevated temperature solution, the solutioncan be cooled relatively quickly (referred to herein as “fast cooling”)by, for example, holding the solution at about 4° C. overnight. Anothermethod can include cooling the solution to ambient temperature at a rateof about 20° C./h (referred to herein as “slow cooling”), thenoptionally allowing the solution to equilibrate overnight at roomtemperature (with or without stirring). In some embodiments, the surfaceof a solution can be scratched with an implement known in the art, suchas, but not limited to, a spatula. In other embodiments, a solution canbe concentrated by methods known in the art, such as in vacuo, or bypassing a stream of gas (inert gases such as argon or nitrogen; ambientair. CO₂, etc.), and in some instances be evaporated to a level ofdryness. Solids obtained by these procedures or variants thereof can berecovered, for example, through filtration techniques or decantation ofany remaining liquid. Identification of the resulting polymorph Form ofa compound of Formula (I), or salt, solvate, or hydrate thereof, can beperformed using any of the techniques (e.g., XRPD, DSC. TGA, etc.)described herein and known in the art.

Form A

In one embodiment, a polymorph provided herein is Form A of a compoundof Formula (I).

FIG. 1 shows a representative X-ray powder diffraction (XRPD) forpolymorph Form A.

In one embodiment, polymorph Form A can be characterized by any one,two, three, four, five, six, seven, eight, nine, ten, or more ofsignificant peak(s) of FIG. 1 . In one embodiment, polymorph Form A canbe characterized as having at least one XRPD peak selected from 2θ=9.6°(±0.2°), 12.2° (±0.2°), and 18.3° (±0.2°). In one embodiment, polymorphForm A can be characterized as having at least one XRPD peak selectedfrom 2θ=9.6° (±0.2°), 12.2° (±0.2°), and 18.3° (±0.2°) in combinationwith at least one XRPD peak selected from 2θ=15.6° (±0.2°) and 19.2°(±0.2°). In another embodiment, polymorph Form A can be characterized ashaving at least one XRPD peak selected from 2θ=9.6° (±0.2°), 12.2°(±0.2°), 15.6° (±0.2°), 18.3° (±0.2°), and 19.2° (±0.2°) in combinationwith at least one XRPD peak selected from 20=9.1° (±0.2°), 9.4° (±0.2°),12.4° (±0.2°), 14.8° (±0.2°), 16.3° (±0.2°), 17.7° (±0.2°), 21.1°(±0.2°), 21.9° (t 0.2°), 24.0° (±0.2°), and 26.9° (±0.2°). In oneembodiment, polymorph Form A can be characterized in that it hassubstantially all of the peaks in its XRPD pattern as shown in FIG. 1 .

FIGS. 12 and 22 shows a differential scanning calorimetry (DSC)thermogram for polymorph Form A. In some embodiments, polymorph Form Acan be characterized as having a endothermic peak at about 238° C. orabout 239° C. In another embodiment, polymorph Form A can becharacterized as having an endothermic peak at about 238° C. or about239° C. and an endothermic peak at about 280° C.

FIG. 22 shows a thermogravimetric analysis (TGA) for polymorph Form A.The lack of feature in the TGA trace indicates significant weight losswas not observed upon heating.

In certain embodiments, Form A can be obtained by fast and slow coolingcrystallization from single solvent systems created by dissolving Form Cin the solvent, including, but not limited to, acetonitrile andn-butanol. In certain embodiments, Form A can be obtained bycrystallization from binary solvent systems comprising ethyl acetate andhexanes. In other embodiments, Form A can be obtained by fast and slowcooling from binary solvent systems created by dissolving Form C in asolvent, such as, but not limited to, acetone, methylethyl ketone, DMF,dioxane, and then adding an anti-solvent, such as, without limitation,dichloromethane. In one embodiment, Form A can also be obtained fromslurries in dichloromethane, acetonitrile, ethanol, and/or isopropylalcohol. In one embodiment, Form A can be obtained from a slurry of FormC, Form D, and/or Form E in acetonitrile.

In one embodiment, Form A is obtained by re-slurrying one or morenon-Form A polymorph(s) in an anhydrous solvent. In one embodiment,non-Form A polymorphs include, without limitation, Form B, Form C, FormD, Form E, Form F, Form G, Form H, Form I, Form J, an amorphous form,and mixtures thereof. For example, in one embodiment, Form A can beobtained by re-slurrying one or more non-Form A polymorph(s) (such as,without limitation, Form C or an amorphous form) in, e.g., chloroform,dichloromethane, isopropyl alcohol, ethanol, or mixtures thereof. Inanother embodiment, Form A can be obtained by re-slurrying a mixture ofForm A, Form B, and Form C in acetonitrile. In one embodiment, Form Acan be obtained by re-slurrying a mixture of Form A, Form C, Form D, andForm E in isopropanol. In one embodiment, Form A can be obtained bycrystallization from a multi-solvent system. In one embodiment, Form Acan be an anhydrate.

Form B

In one embodiment, a polymorph provided herein is Form B of a compoundof Formula (I).

FIG. 2 shows a representative XRPD for polymorph Form B.

In one embodiment, polymorph Form B can be characterized by any one,two, three, four, five, six, seven, eight, nine, ten, or more ofsignificant peak(s) of FIG. 2 . In one embodiment, polymorph Form B canbe characterized as having at least one XRPD peak selected from 2θ=7.9°(±0.2°), 13.4° (±0.2°), and 23.4° (±0.2°). In one embodiment, polymorphForm B can be characterized as having at least one XRPD peak selectedfrom 2θ=7.9° (±0.2°), 13.4° (±0.2°), and 23.4° (±0.2°) in combinationwith at least one XRPD peak selected from 2θ=14.0° (±0.2°) and 15.0°(±0.2°). In another embodiment, polymorph Form B can be characterized ashaving at least one XRPD peak selected from 2θ=7.9° (±0.2°), 13.4°(±0.2°), 14.0° (±0.2°), 15.0° (±0.2°), and 23.4° (±0.2°) in combinationwith at least one XRPD peak selected from 20=9.5° (0.2°), 12.7° (±0.2°),13.6° (±0.2°), 14.2° (±0.2°), 15.7° (±0.2°), 19.0° (±0.2°), 22.3°(±0.2°), 24.2° (±0.2°), 24.8° (±0.2°), and 26.9° (±0.2°). In oneembodiment, polymorph Form B can be characterized in that it hassubstantially all of the peaks in its XRPD pattern as shown in FIG. 2 .

FIG. 13 shows a differential scanning calorimetry (DSC) thermogram forpolymorph Form B. In some embodiments, polymorph Form B can becharacterized by having a endothermic peak at about 280° C. to about283° C. In one embodiment, the DSC endothermic peak is about 281° C. Inone embodiment, the DSC endothermic peak is about 282° C. In oneembodiment, the DSC endothermic peak is about 283° C.

In certain embodiments, Form B can be produced from Form A upon anisothermal hold at about 250° C. followed by cooling to roomtemperature. In one embodiment, Form B can be produced from Form C upona similar thermal conversion procedure. In certain embodiments, Form Bis produced by thermal conversion from a non-Form B polymorph, such as,without limitation, Form A, Form C, Form D, Form E, Form F, Form G, FormH, Form I, Form J, an amorphous form, and mixtures thereof. In oneembodiment, Form B can be an anhydrate.

Form C

In one embodiment, a polymorph provided herein is Form C of a compoundof Formula (I).

FIG. 3 shows a representative XRPD for polymorph Form C.

In one embodiment, polymorph Form C can be characterized by any one,two, three, four, five, six, seven, eight, nine, ten, or more ofsignificant peak(s) of FIG. 3 . In one embodiment, Form C can becharacterized by having at least one XRPD peak selected from 2θ=10.5°(±0.2°), 13.7° (±0.2°), and 24.5° (±0.2°). In another embodiment, Form Ccan be characterized by having at least one XRPD peak selected from2θ=10.4° (±0.2°), 13.3° (±0.2°), and 24.3° (±0.2°). In one embodiment,polymorph Form C can be characterized as having at least one XRPD peakselected from 2θ=10.4° (±0.2°), 13.3° (±0.2°), and 24.3° (±0.2°) incombination with at least one XRPD peak selected from 2θ=6.6° (±0.2°)and 12.5° (0.2°). In another embodiment, polymorph Form C can becharacterized as having at least one XRPD peak selected from 2θ=6.6°(±0.2°), 10.4° (±0.2°), 12.5° (±0.2°), 13.3° (±0.2°), and 24.3° (±0.2°)in combination with at least one XRPD peak selected from 2θ=8.8°(±0.2°), 9.9° (±0.2°), 13.4° (±0.2°), 15.5° (±0.2°), 16.9° (±0.2°),19.8° (±0.2°), 21.3° (±0.2°), 23.6° (±0.2°), 25.3° (±0.2°), and 27.9°(±0.2°). In one embodiment, polymorph Form C can be characterized inthat it has substantially all of the peaks in its XRPD pattern as shownin FIG. 3 .

FIGS. 14 and 23 show exemplary differential scanning calorimetry (DSC)thermograms for polymorph Form C. In some embodiments, polymorph Form Ccan be characterized as having an endothermic peak at about 203° C. Insome embodiments, polymorph Form C can be characterized as having anendothermic peak at about 206° C. or about 208° C. In anotherembodiment, polymorph Form C can be characterized as having anendothermic peak in the range of about 203° C. to about 208° C., and atleast one peak selected from an exothermic peak in the range of about251° C. to about 254° C., and an endothermic peak in the range of about281° C. to about 283° C. In one embodiment, polymorph Form C can becharacterized as having an endothermic peak at about 208° C., anexothermic peak at about 254° C., and an endothermic peak at about 283°C. The peak position variability is within expected observance usingthis thermographic analysis as described further below in the examplessection. For instance, peak position can be affected by samplepreparation, rate of temperature increase, and instrument utilized,among other factors known in the art.

In some embodiments, polymorph Form C can be characterized by athermogravimetric analysis (TGA). In one embodiment, a weight loss ofabout 1.7% wt can be observed at about 80° C. and a weight loss of about0.2% wt can be observed at about 190° C.

In certain embodiments, Form C is obtained in a mixture with non-Form Cpolymorphs, such as, without limitation, Form A, Form B, Form D, Form E,Form F, Form G, Form H, Form I, Form J, an amorphous form, and mixturesthereof. For example, in certain embodiments, Form C is present as acomposition further comprising one or more non-Form C polymorphs. Theamount of non-Form C polymorphs in the composition can vary. Forexample, in certain embodiments, the weight ratio of polymorph Form C tothe total amount of one or more non-Form C polymorph(s) is greater thanabout 7:1, greater than about 8:1, greater than about 9:1, greater thanabout 9.5:1, or greater than about 99:1. Similarly, when formulated inpharmaceutical compositions, various amounts of non-C polymorph form canbe present. In certain embodiments, the weight ratio of polymorph Form Cto the total amount of one or more non-C polymorphs in a pharmaceuticalcomposition is greater than about 7:1, greater than about 8:1, greaterthan about 9:1, greater than about 9.5:1, or greater than about 99:1.

In certain embodiments, Form C is obtained from direct workup of thesynthetic step producing the compound of Formula (I), and non-C Formsare not obtained, or are obtained as a minority component. In certainembodiments, the final workup of the reaction mixture includes water toremove any soluble salts formed during the reaction. In certainembodiments, a seed crystal can be added to avoid or reduce oiling outof the compound of Formula (I). Seed crystals of any form can be used.In one embodiment, the seed crystal is of polymorph Form C. In certainembodiments, one or more non-C Forms ae obtained with or withoutrecovery and/or purification, followed by subsequent conversion of theone or more non-C Forms to Form C.

In certain embodiments, Form C is produced by placing Form A in water toform a slurry for about 18-24 hours, or until a certain amount ofconversion of Form A to Form C has occurred. In certain embodiments,Form C is produced by placing Form A in water or a water-containingsolvent system. Upon exposure to water or a water-containing solventsystem, the combination can form a slurry. The combination of Form A andwater or water-containing solvent system can be stirred, optionally withheating, until conversion of Form C has occurred. In certainembodiments, Form A is exposed to water and other solvents are excluded.In some embodiments, Form C can be obtained by slurrying Form D and/orForm E in water. In some embodiments, Form C can be obtained byslurrying a mixture of Form A, Form C, Form D, and Form E in water. Inone embodiment, Form C can be obtained by slurrying a mixture of Form Band Form C in water.

In certain embodiments, the solvent system is a Ci-Ce alcohol withwater. In certain embodiments, the solvent system is a water-misciblealcohol with water. In certain embodiments, the solvent system is anon-alcohol water-miscible solvent with water. In certain embodiments,Form C is produced by fast or slow cooling from binary solvent systems,including, without limitation, ethanol, isopropyl alcohol,tetrahydrofuran, acetone, dioxane, NMP, DME, and DMF as primary solvent,and an anti-solvent, such as, without limitation, water. In certainembodiments, the solvent system is ethanol or 2-propanol with water. Insome embodiments, Form C can be obtained by slurrying a mixture of FormA, Form B and Form C in ethanol and water.

Where a solvent in addition to water is used, the ratio of solvent towater can vary from about 100/1 to about 1/100. For example, the ratioof solvent to water can be selected from about 100/1, about 90/I, about80/1, about 70/1, about 60/1, about 50/1, about 40/1, about 30/1, about20/1, about 10/1, about 9/1, about 8/1, about 7/1, about 6/1, about 5/1,about 4/1, about 3/1, about 2/1, about 1.5/1, about 1/1, about 1/1.5,about 1/2, about 1/3, about 1/4, about 1/5, about 1/6, about 1/7, about1/8, about 1/9, about 1/10, about 1/20, about 1/30, about 1/40, about1/50, about 1/60, about 1/70, about 1/80, about 1/90, and about 1/100.In certain embodiments, the ratio of ethanol or isopropyl alcohol towater can be about 7/4, about 9/7, about 7/10, or the like. The totalamount of solvent or solvent system can be selected from about 0.1volumes (e.g., liters/kg), about 0.5 volumes, about 1 volume, about 2volumes, about 3 volumes, 4 about volumes, about 5 volumes, about 6volumes, about 7 volumes, about 8 volumes, about 9 volumes, about 10volumes, about 11 volumes, about 12 volumes, about 13 volumes, about 14volumes, about 15 volumes, about 16 volumes, about 17 volumes, about 18volumes, about 19 volumes, about 20 volumes, about 30 volumes, about 40volumes, about 50 volumes, or more. In certain embodiments, the solventsystem is ethanol/water. In certain embodiments, the solvent system isisopropyl alcohol/water.

In some embodiments, a method of preparing Form C includes preparing aslurry of Form C in dichloromethane to effect a polymorph change to FormA. After recovery of the solids by filtration, the polymorph Form A canbe added to water to form a slurry. After stirring for a period of time,(e.g., about 3-12 hours), the slurry can be filtered and polymorph FormC can be recovered.

In certain embodiments, Form C is obtained by recrystallization of anon-C Form, including complete dissolution of the non-C Form followed byfiltration to remove any insoluble particles, and subsequentcrystallization to yield Form C. In certain embodiments, completedissolution and filtration is not performed, in which case a slurry isformed which converts to Form C without complete dissolution of one ormore non-C Forms. In one embodiment, Form C can be obtained bycrystallization from a multi-solvent system. In some embodiments, Form Cexhibits better flow properties than that of Form A. In certainembodiments, Form C is a channel hydrate.

Form D

In one embodiment, a polymorph provided herein is Form D of a compoundof Formula (I).

FIG. 4 shows a representative XRPD for polymorph Form D.

In one embodiment, polymorph Form D can be characterized by any one,two, three, four, five, six, seven, eight, nine, ten, or more ofsignificant peak(s) of FIG. 4 . In one embodiment, polymorph Form D canbe characterized as having at least one XRPD peak selected from 2θ=11.4°(±0.2°), 17.4° (±0.2°), and 22.9° (±0.2°). In one embodiment, polymorphForm D can be characterized as having at least one XRPD peak selectedfrom 2θ=11.4° (0.2°), 17.4° (±0.2°), and 22.9° (±0.2°) in combinationwith at least one XRPD peak selected from 2θ=9.20 (±0.2°) and 18.3°(±0.2°). In another embodiment, polymorph Form D can be characterized ashaving at least one XRPD peak selected from 2θ=9.2° (±0.2°), 11.4°(0.2°), 17.4° (±0.2°), 18.3° (0.2°), and 22.9° (±0.2°) in combinationwith at least one XRPD peak selected from 2θ=9.8° (±0.2°), 12.2°(±0.2°), 15.8° (±0.20), 16.2° (±0.2°), 16.8° (±0.2°), 18.9° (±0.2°),19.9° (±0.2°), 20.0° (±0.2°), 24.9° (±0.2°), and 29.3° (±0.20). In oneembodiment, polymorph Form D can be characterized in that it hassubstantially all of the peaks in its XRPD pattern as shown in FIG. 4 .

FIG. 15 shows a differential scanning calorimetry (DSC) thermogram forpolymorph Form D. In some embodiments, polymorph Form D can becharacterized as having an endothermic peak at about 260° C. In anotherembodiment, polymorph Form D can be characterized as having anendothermic peak at about 260° C. and an endothermic peak at about 283°C.

In some embodiments, polymorph Form D can be characterized bythermogravimetric analysis (IGA). In one embodiment, a weight loss ofabout 0.2% wt can be observed at about 150° C.

In certain embodiments, Form D can be obtained by fast coolingcrystallization from a single solvent system, including, but not limitedto, tetrahydrofuran, methyl ethyl ketone, dioxane, or dimethylformamide.In certain embodiments, Form D can be obtained by slow coolingcrystallization from a single solvent system, including, but not limitedto, tetrahydrofuran, methyl ethyl ketone, or dioxane. In one embodiment,Form D can be obtained by slurrying Form C and/or Form E in methyl ethylketone. In one embodiment, Form D can be obtained by slurrying a mixtureof Form A, Form B and Form C in methyl ethyl ketone. In anotherembodiment, Form D can be obtained by slurrying a mixture of Form B andForm D in methyl ethyl ketone.

In certain embodiments, Form D can be obtained by fast coolingcrystallization from a binary solvent system with, for example,tetrahydrofuran, dioxane, or DMF as the primary solvent and ananti-solvent, such as, without limitation, MTBE. In certain embodiments,Form D can be obtained by fast cooling crystallization from a binarysolvent system with, for example, tetrahydrofuran, isopropanol, or DMFas the primary solvent and an anti-solvent, such as, without limitation,toluene. In one embodiment, Form D can be obtained by fast coolingcrystallization from a binary solvent system with, for example,tetrahydrofuran as the primary solvent and dichloromethane as theanti-solvent. In certain embodiments, Form D can be obtained by slowcooling crystallization from a binary solvent system with, for example,methyl ethyl ketone or DMF as the primary solvent and MTBE as theanti-solvent. In certain embodiments, Form D can be obtained by slowcooling crystallization from a binary solvent system with, for example,tetrahydrofuran or DME as the primary solvent and dichloromethane as theanti-solvent. In certain embodiments, Form D can be obtained by slowcooling crystallization from a binary solvent system with, for example,isopropanol, NNP, or DME as the primary solvent and toluene as theanti-solvent.

In one embodiment, Form D can be obtained by crystallization from amulti-solvent system. In certain embodiments, Form D can be formed byslurry in methyl ethyl ketone of a non-Form D polymorph, such as,without limitation, Forms A, B, C, or E. In one embodiment, Form D canbe an anhydrate.

Form E

In one embodiment, a polymorph provided herein is Form E of a compoundof Formula (I).

FIG. 5 shows a representative XRPD for polymorph Form E.

In one embodiment, polymorph Form E can be characterized by any one,two, three, four, five, six, seven, eight, nine, ten, or mom ofsignificant peak(s) of FIG. 5 . In one embodiment, polymorph Form E canbe characterized as having at least one XRPD peak selected from 2θ=6.7°(±0.2°), 9.3° (±0.2°), and 24.4° (±0.2°). In one embodiment, polymorphForm E can be characterized as having at least one XRPD peak selectedfrom 2θ=6.7° (±0.2°), 9.3° (±0.2°), and 24.4° (±0.2) in combination withat least one XRPD peak selected from 2θ=12.7° (±0.2°) and 13.9° (±0.2°).In another embodiment, polymorph Form E can be characterized as havingat least one XRPD peak selected from 2θ=6.7° (±0.2°), 9.3° (±0.2°),12.7° (±0.2°), 13.9° (±0.2°), and 24.4° (±0.2°) in combination with atleast one XRPD peak selected from 20=12.4° (±0.2°), 13.3° (±0.2°), 14.3°(±0.2°), 15.5° (±0.2°), 17.4° (±0.2°), 18.5° (±0.2°), 22.0° (±0.2°),23.9° (±0.2°), 24.1° (±0.2°), and 26.4° (±0.2°). In one embodiment,polymorph Form E can be characterized in that it has substantially allof the peaks in its XRPD pattern as shown in FIG. 5 .

FIG. 16 shows a differential scanning calorimetry (DSC) thermogram forpolymorph Form E. In some embodiments, polymorph Form E can becharacterized as having an endothermic peak at about 131° C., anendothermic peak at about 263° C., an exothermic peak at about 267° C.,and an endothermic peak at about 282° C.

In some embodiments, polymorph Form E can be characterized bythermogravimetric analysis (TGA). In one embodiment, a weight loss ofabout 0.7% wt can be observed at about 80° C. and a weight loss of about1.3% wt can be observed at about 130° C.

In certain embodiments, Form E can be obtained from Form A by slowcooling crystallization from a single solvent system with, for example,methanol. In certain embodiments, Form E can be obtained by either fastor slow cooling crystallization from a binary solvent system with, forexample, methanol as the primary solvent and water as the anti-solvent.In one embodiment, Form E can be obtained by crystallization from amulti-solvent system. In one embodiment, Form E can be an anhydrate.

Form F

In one embodiment, a polymorph provided herein is Form F of a compoundof Formula (I).

FIG. 6 shows a representative XRPD for polymorph Form F.

In one embodiment, polymorph Form F can be characterized by any one,two, three, four, five, six, seven, eight, nine, ten, or more ofsignificant peak(s) of FIG. 6 . In one embodiment, polymorph Form F canbe characterized as having at least one XRPD peak selected from 2θ=9.6°(±0.2°), 17.3° (±0.2°), and 24.60 (0.2°). In one embodiment, polymorphForm F can be characterized as having at least one XRPD peak selectedfrom 2θ=9.60 (±0.2°), 17.3° (±0.2°), and 24.6° (±0.2°) in combinationwith at least one XRPD peak selected from 2θ=14.0° (±0.2°) and 19.2°(±0.2°). In another embodiment, polymorph Form F can be characterized ashaving at least one XRPD peak selected from 2θ=9.6° (±0.2°), 14.0°(±0.2°), 17.3° (±0.2°), 19.2° (±0.2°), and 24.6° (±0.2°) in combinationwith at least one XRPD peak selected from 2θ=12.4° (±0.2°), 16.1°(±0.2°), 16.6° (±0.2°), 17.1° (±0.2°), 20.8° (±0.2°), 21.5° (±0.2°),22.0° (±0.2°), 24.3° (±0.2°), 25.2° (±0.2°), and 25.4° (±0.2°). In oneembodiment, polymorph Form F can be characterized in that it hassubstantially all of the peaks in its XRPD pattern as shown in FIG. 6 .

FIGS. 17 and 24 show exemplary differential scanning calorimetry (DSC)endotherm analyses for Form F. In some embodiments, polymorph Form F canbe characterized as having an endothermic peak at about 181° C., anendothermic peak at about 160° C., an exothermic peak at about 266° C.,and an endothermic peak at about 282° C.

FIG. 24 shows a thermogravimetric analysis (TGA) for polymorph Form F.In some embodiments, polymorph Form F can be characterized by TGA. Inone embodiment, a weight loss of about 15.8% wt can be observed at about150° C., and a weight loss of about 2.8% wt can be observed at about180° C.

In certain embodiments, Form F can be obtained by fast coolingcrystallization from a binary solvent system with, for example, NMP asthe primary solvent and MBTE as the anti-solvent. In certainembodiments, Form F can be obtained by slow cooling crystallization froma binary solvent system with, for example, NMP as the primary solventand MBTE as the anti-solvent. In some embodiments, Form F is an NMPsolvate. In certain embodiments, MTBE can be present as an anti-solvent.In one embodiment, Form F can be obtained by crystallization from amulti-solvent system.

Form G

In one embodiment, a polymorph provided herein is Form G of a compoundof Formula (I).

FIG. 7 shows a representative XRPD for polymorph Form G.

In one embodiment, polymorph Form G can be characterized by any one,two, three, four, five, six, seven, eight, nine, ten, or more ofsignificant peak(s) of FIG. 7 . In one embodiment, polymorph Form G canbe characterized as having at least one XRPD peak selected from 2θ=6.7°(±0.2°), 9.5° (±0.2°), and 19.0° (±0.2°). In one embodiment, polymorphForm G can be characterized as having at least one XRPD peak selectedfrom 2θ=6.7° (10.2°), 9.5° (±0.2°), and 19.0° (±0.2°) in combinationwith at least one XRPD peak selected from 2θ=10.6° (±0.2°) and 19.6°(±0.2°). In another embodiment, polymorph Form G can be characterized ashaving at least one XRPD peak selected from 2θ=6.7° (±0.2°), 9.5°(±0.2°), 10.6° (±0.2°), 19.0° (±0.2°), and 19.6° (±0.2°) in combinationwith at least one XRPD peak selected from 2θ=13.4° (±0.2°), 15.0°(0.2°), 15.8° (±0.2), 17.8° (0.2°), 20.7° (±0.2°), 21.2° (±0.2°), 22.8°(±0.2°), 23.8° (±0.2°), 24.3° (±0.2°), and 25.6° (±0.2°). In oneembodiment, polymorph Form G can be characterized in that it hassubstantially all of the peaks in its XRPD pattern as shown in FIG. 7 .

FIG. 18 shows a differential scanning calorimetry (DSC) thermogram forpolymorph Form G. In some embodiments, polymorph Form G can becharacterized as having an endothermic peak at about 162° C. In anotherembodiment, polymorph Form G can be characterized as having anendothermic peak at about 162° C., an exothermic peak at about 241° C.,and an endothermic peak at about 281° C.

In some embodiments, polymorph Form G can be characterized bythermogravimetric analysis (TGA). In one embodiment, a weight loss ofabout 18.5% wt can be observed at about 160° C.

In certain embodiments, Form G can be obtained by fast coolingcrystallization from a binary solvent system with, for example, ethanol,isopropyl alcohol, or methanol as the primary solvent. In certainembodiments, MTBE can be present as an anti-solvent. In one embodiment,Form G is an MTBE solvate. In one embodiment, Form G can be obtained bycrystallization from a multi-solvent system.

Form H

In one embodiment, a polymorph provided herein is Form H of a compoundof Formula (I).

FIG. 8 shows a representative XRPD for polymorph Form H.

In one embodiment, polymorph Form H can be characterized by any one,two, three, four, five, six, seven, eight, nine, ten, or mom ofsignificant peak(s) of FIG. 8 . In one embodiment, polymorph Form H canbe characterized as having at least one XRPD peak selected from 2θ=8.9°(±0.2°), 9.2° (±0.2°), and 14.1° (±0.2°). In one embodiment, polymorphForm H can be characterized as having at least one XRPD peak selectedfrom 2θ=8.9° (±0.2°), 9.2° (±0.2°), and 14.1° (±0.2°) in combinationwith at least one XRPD peak selected from 2θ=17.3° (±0.2°) and 18.5°(±0.2°). In another embodiment, polymorph Form H can be characterized ashaving at least one XRPD peak selected from 2θ=8.9° (±0.2°), 9.2°(±0.2°), 14.1° (±0.2°), 17.3° (±0.2°), and 18.5° (±0.2°) in combinationwith at least one XRPD peak selected from 2θ=7.1^(°) (±0.2°), 10.6°(±0.2°), 11.3° (+0.2°), 11.6° (+0.2°), 16.2° (±0.2°), 18.3° (±0.2°),18.8° (±0.2°), 20.3° (±0.2°), 21.7° (±0.2°), and 24.7° (±0.2°). In oneembodiment, polymorph Form H can be characterized in that it hassubstantially all of the peaks in its XRPD pattern as shown in FIG. 8 .

FIG. 19 shows a differential scanning calorimetry (DSC) thermogram forpolymorph Form H. In some embodiments, polymorph Form H can becharacterized as having an endothermic peak at about 128° C. and anendothermic peak at about 258° C. In another embodiment, polymorph FormH can be characterized as having an endothermic peak at about 128° C.,an endothermic peak at about 258° C., and an endothermic peak at about282° C.

In some embodiments, polymorph Form H can be characterized bythermogravimetric analysis (TGA). In one embodiment, a weight loss ofabout 7.5% wt can be observed at about 130° C.

In certain embodiments, Form H can be obtained by slow coolingcrystallization from a binary solvent system with, for example, dioxaneas the primary solvent, and an anti-solvent, such as, withoutlimitation, MTBE. In one embodiment, Form H is an MTBE solvate. In oneembodiment, Form H can be obtained by crystallization from amulti-solvent system.

Form I

In one embodiment, a polymorph provided herein is Form I of a compoundof Formula (I).

FIG. 9 shows a representative XRPD for polymorph Form I.

In one embodiment, polymorph Form I can be characterized by any one,two, three, four, five, six, seven, eight, nine, ten, or more ofsignificant peak(s) of FIG. 9 . In one embodiment, polymorph Form I canbe characterized as having at least one XRPD peak selected from 2θ=9.7°(±0.2°), 19.3° (±0.2°), and 24.5° (±0.2°). In one embodiment, polymorphForm I can be characterized as having at least one XRPD peak selectedfrom 2θ=9.7° (±0.2°), 19.3° (±0.2°), and 24.5° (±0.2°) in combinationwith at least one XRPD peak selected from 2θ=11.4° (±0.2°) and 14.2°(±0.2°). In another embodiment, polymorph Form I can be characterized ashaving at least one XRPD peak selected from 2θ=9.7° (±0.2°), 11.4°(±0.2°), 14.2° (±0.2°), 19.3° (±0.2°), and 24.5° (±0.2°) in combinationwith at least one XRPD peak selected from 2θ=9.2° (±0.2°), 14.7°(±0.2°), 15.5° (±0.2°), 16.7° (±0.2°), 17.3° (±0.2°), 18.4° (±0.2°),21.4° (±0.2°), 22.9° (±0.2°), 29.1° (±0.2°), and 34.1° (±0.2°). In oneembodiment, polymorph Form I can be characterized in that it hassubstantially all of the peaks in its XRPD pattern as shown in FIG. 9 .

FIG. 20 shows a differential scanning calorimetry (DSC) thermogram forpolymorph Form I. In some embodiments, polymorph Form I can becharacterized as having an endothermic peak at about 208° C. and anendothermic peak at about 263° C.

In some embodiments, polymorph Form I can be characterized bythermogravimetric analysis (TGA). In one embodiment, a weight loss ofabout 10.5% wt can be observed at about 130° C. and a weight loss ofabout 0.8% wt can be observed at about 200° C.

In certain embodiments, Form I can be obtained by slow coolingcrystallization from a binary solvent system, including, withoutlimitation, acetone, MEK, or dioxane as the primary solvent, and ananti-solvent, such as, without limitation, toluene. In one embodiment,Form I is a hemi-toluene solvate. In one embodiment, Form I can beobtained by crystallization from a multi-solvent system.

Form J

In one embodiment, a polymorph provided herein is Form J of a compoundof Formula (I).

FIG. 10 shows a representative XRPD for Polymorph Form J.

In one embodiment, polymorph Form J can be characterized by any one,two, three, four, five, six, seven, eight, nine, ten, or more ofsignificant peak(s) of FIG. 10 . In one embodiment, polymorph Form J canbe characterized as having at least one XRPD peak selected from 2θ=9.1°(±0.2°), 17.3° (±0.2°), and 18.3° (±0.2°). In one embodiment, polymorphForm J can be characterized as having at least one XRPD peak selectedfrom 2θ=9.1° (±0.2°), 17.3° (±0.2°), and 18.3° (±0.2°) in combinationwith at least one XRPD peak selected from 2θ=16.4° (±0.2°) and 17.9°(0.2°). In another embodiment, polymorph Form J can be characterized ashaving at least one XRPD peak selected from 2θ=9.1° (±0.2°), 16.4°(±0.2°), 17.3° (±0.2°), 17.9° (±0.2°), and 18.3° (±0.2°) in combinationwith at least one XRPD peak selected from 2θ=9.4° (±0.2°), 10.1°(±0.2°), 10.7° (±0.2°), 14.0° (±0.2°), 14.3° (±0.2°), 15.5° (±0.2°),16.9° (±0.2°), 19.9° (±0.2°), 24.0° (±0.2°), and 24.7° (±0.2°). In oneembodiment, polymorph Form J can be characterized in that it hassubstantially all of the peaks in its XRPD pattern as shown in FIG. 10 .

FIG. 21 shows a differential scanning calorimetry (DSC) thermogram forpolymorph Form J. In some embodiments, polymorph Form J can becharacterized as having an endothermic peak at about 259° C. In anotherembodiment, polymorph Form J can be characterized as having anendothermic peak at about 121° C., an endothermic peak at about 185° C.,an endothermic peak at about 259° C. and an endothermic peak at about282° C.

In some embodiments, polymorph Form J can be characterized bythermogravimetric analysis (TGA). In one embodiment, a weight loss ofabout 10.8% wt can be observed at about 100° C.

In certain embodiments, Form J can be obtained by slow coolingcrystallization from a binary solvent system, including, withoutlimitation, DMF as the primary solvent, and an anti-solvent, such as,without limitation, toluene. In one embodiment, Form J is a hemi-toluenesolvate. In one embodiment, Form J can be obtained by crystallizationfrom a multi-solvent system.

Amorphous Forms

In one embodiment, an amorphous form of a compound of Formula (I) isprovided herein.

FIG. 11 shows a representative XRPD for an amorphous form. The lack ofdiffraction peaks indicates the lack of crystallinity in the amorphousform.

In one embodiment, an amorphous form of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or hydrate thereof, can bemade by dissolution of a crystalline form followed by removal of solventunder conditions in which stable crystals are not formed. For example,solidification can occur by rapid removal of solvent, by rapid additionof an anti-solvent (causing the amorphous form to precipitate out ofsolution), or by physical interruption of the crystallization process.Grinding processes can also be used. In other embodiments, an amorphousform of a compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, or hydrate thereof, can be made using a process orprocedure described herein elsewhere.

In certain embodiments, an amorphous form can be obtained by fastcooling from a single solvent system, such as, e.g., ethanol, isopropylalcohol, t-amyl alcohol, n-butanol, methanol, acetone, ethyl acetate, oracetic acid. In certain embodiments, an amorphous form can be obtainedby slow cooling from a single solvent system, such as, e.g., ethanol,isopropyl alcohol, t-amyl alcohol, or ethyl acetate.

In certain embodiments, an amorphous form can be obtained by fastcooling from a binary solvent system, for example, with acetone or DMEas the primary solvent. In certain embodiments, an amorphous form can beobtained by slow cooling from a binary solvent system, for example, withethanol, isopropyl alcohol, THF, acetone, or methanol as the primarysolvent. In some embodiments, an amorphous form can be obtained bydissolution of a compound of Formula (I) in t-butanol and water atelevated temperature, followed by cooling procedures to afford anamorphous solid form.

In some embodiments, the amorphous compound of Formula (I) is a salt,solvate, or hydrate thereof. In some embodiments, the amorphous compoundof Formula (I) is a pharmaceutically acceptable salt, solvate, orhydrate thereof. In one embodiment, the amorphous compound of Formula(I) can contain an amount of one or more partially crystalline orcrystalline compounds of Formula (I). Non-limiting examples includeamorphous compounds of Formula (I) containing less than about 10% of oneor more partially crystalline or crystalline compounds of Formula (I),less than about 9/6 of one or more partially crystalline or crystallinecompounds of Formula (I), less than about 8% of one or more partiallycrystalline or crystalline compounds of Formula (I), less than about 7%of one or more partially crystalline or crystalline compounds of Formula(I), less than about 6% of one or more partially crystalline orcrystalline compounds of Formula (I), less than about 5% of one or morepartially crystalline or crystalline compounds of Formula (I), less thanabout 4% of one or more partially crystalline or crystalline compoundsof Formula (I), less than about 3% of one or more partially crystallineor crystalline compounds of Formula (I), less than about 2% of one ormore partially crystalline or crystalline compounds of Formula (I), lessthan about 1% of one or more partially crystalline or crystallinecompounds of Formula (I), less than about 0.5% of one or more partiallycrystalline or crystalline compounds of Formula (I), less than about0.1% of one or more partially crystalline or crystalline compounds ofFormula (I), and less than about 0.01% of one or more partiallycrystalline or crystalline compounds of Formula (I). In someembodiments, the amorphous compound of Formula (I), or a salt, solvate,or hydrate thereof, contains one or more partially crystallinecompounds, or a salt, solvate, or hydrate thereof. In some embodiments,the amorphous compound of Formula (I), or a salt, solvate, or hydratethereof, contains one or more crystalline compounds of Formula (I), or asalt, solvate, or hydrate thereof.

Salt Forms

In certain embodiments, a compound of Formula (I) provided herein is apharmaceutically acceptable salt, or a solvate or hydrate thereof. Inone embodiment, pharmaceutically acceptable acid addition salts of acompound provided herein can be formed with inorganic acids and organicacids. Inorganic acids from which salts can be derived include, but arenot limited to, hydrochloric acid, hydrobromic acid, sulfuric acid,nitric acid, phosphoric acid, and the like. Organic acids from whichsalts can be derived include, but are not limited to, acetic acid,propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid,malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and thelike. In other embodiments, if applicable, pharmaceutically acceptablebase addition salts of a compound provided herein can be formed withinorganic and organic bases. Inorganic bases from which salts can bederived include, but are not limited to, sodium, potassium, lithium,ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum,and the like. Organic bases from which salts can be derived include, butare not limited to, primary, secondary, and tertiary amines, substitutedamines including naturally occurring substituted amines, cyclic amines,basic ion exchange resins, and the like. Exemplary bases include, butare not limited to, isopropylamine, trimethylamine, diethylamine,triethylamine, tripropylamine, and ethanolamine. In some embodiments, apharmaceutically acceptable base addition salt is ammonium, potassium,sodium, calcium, or magnesium salt. In one embodiment, bis salts (i.e.,two counterions) and higher salts (e.g., three or more counterions) areencompassed within the meaning of pharmaceutically acceptable salts.

In certain embodiments, salts of a compound of Formula (I) can be formedwith, e.g., L-tartaric acid, p-toluenesulfonic acid, D-glucaronic acid,ethane-1,2-disulfonic acid (EDSA), 2-naphthalenesulfonic acid (NSA),hydrochloric acid (HCl) (mono and bis), hydrobromic acid (HBr), citricacid, naphthalene-1,5-disulfonic acid (NDSA), DL-mandelic acid, fumaricacid, sulfuric acid, maleic acid, methanesulfonic acid (MSA),benzenesulfonic acid (BSA), ethanesulfonic acid (ESA), L-malic acid,phosphoric acid, and aminoethanesulfonic acid (taurine).

III. Compositions

Provided herein are compositions, including pharmaceutical compositions,comprising one or more polymorphs or amorphous forms of the compound ofFormula (I), or their pharmaceutically acceptable forms (e.g.,pharmaceutically acceptable salts, hydrates, solvates, chelates,non-covalent complexes, isomers, prodrugs, and isotopically labeledderivatives) thereof as provided herein. In some embodiments, providedherein are pharmaceutical compositions comprising polymorph Form C, orits pharmaceutically acceptable salts, solvates and hydrates thereof,and one or more pharmaceutically acceptable excipients. In someembodiments, provided herein are pharmaceutical compositions comprisingpolymorph Form C and polymorph Form A. or their pharmaceuticallyacceptable salts, solvates and hydrates thereof, and one or morepharmaceutically acceptable excipients, wherein the ratio of polymorphForm C to polymorph Form A is greater than about 9:1. In someembodiments, provided herein are pharmaceutical compositions comprisingone or more of polymorph Forms A, B, C, D, E, F, G, H, I, and J, oramorphous compound of Formula (I), or their pharmaceutically acceptablesalts, solvates and hydrates thereof, or mixtures thereof, and one ormore pharmaceutically acceptable excipients. In other embodiments,provided herein are pharmaceutical compositions comprising polymorphForm C and at least one non-Form C polymorph selected from Form A, FormB, Form D, Form E, Form F, Form G, Form H, Form I, Form J, or anamorphous form of a compound of Formula (I), or a salt, solvate, orhydrate thereof, and one or more pharmaceutically acceptable excipients.

In certain embodiments, the ratio of a polymorph, such as Form C, to allother polymorphs in a composition provided herein can be greater thanabout 5:1, about 6:1, about 7:1, about 8:1, about 9:1, or more.

In certain embodiments, the pharmaceutical compositions provided hereinare typically formulated to provide a therapeutically effective amountof a compound provided herein (e.g., a particular polymorph providedherein) as the active ingredient, or pharmaceutically acceptable salts,hydrates, solvates, chelates, esters, non-covalent complexes, isomers,prodrugs, and isotopically labeled derivatives thereof. In someembodiments, the pharmaceutical compositions contain one or morepharmaceutically acceptable salts, solvates, hydrates, and/orcoordination complexs thereof, and one or more pharmaceuticallyacceptable excipients, such as carriers (including inert solid diluentsand fillers), diluents (including sterile aqueous solution and variousorganic solvents), permeation enhancers, solubilizers, and/or adjuvants.

In certain embodiments, the pharmaceutical compositions provided hereincan be administered alone or in combination with one or more otheragents, which are also typically administered in a form of apharmaceutical composition. In some embodiments, a polymorph providedherein and other agent(s) can be mixed into a preparation or bothcomponents can be formulated into separate preparations to use them incombination separately or at the same time.

In one embodiment, administration of polymorphs or pharmaceuticalcompositions provided herein can be effected by any method that enablesdelivery of polymorphs or pharmaceutical compositions to the site ofaction. These methods include, e.g., oral routes, intraduodenal routes,parenteral injection (including intravenous, intraarterial,subcutaneous, intramuscular, intravascular, intraperitoneal orinfusion), topical routes (e.g., transdermal application), rectaladministration, via local delivery by catheter or stent or throughinhalation. In one embodiment, polymorphs can also be administeredintraadiposally or intrathecally.

Pharmaceutical compositions can be specially formulated foradministration in solid or liquid form, including those adapted for thefollowing: oral administration, for example, drenches (aqueous ornon-aqueous solutions or suspensions), tablets (e.g., those targeted forbuccal, sublingual, and systemic absorption), capsules, boluses,powders, granules, pastes for application to the tongue, andintraduodenal routes; parenteral administration, including intravenous,intraarterial, subcutaneous, intramuscular, intravascular,intraperitoneal or infusion as, for example, a sterile solution orsuspension, or sustained-release formulation; topical application, forexample, as a cream, ointment, or a controlled-release patch or sprayapplied to the skin; intravaginally or intrarectally, for example, as apessary, cream, stent or foam; sublingually; ocularly; pulmonarily;local delivery by catheter or stent; intrathecally, or nasally.

Examples of suitable aqueous and nonaqueous carriers which can beemployed in pharmaceutical compositions include water, ethanol, polyols(such as glycerol, propylene glycol, polyethylene glycol, and the like),and suitable mixtures thereof, vegetable oils, such as olive oil, andinjectable organic esters, such as ethyl oleate. Proper fluidity can bemaintained, for example, by the use of coating materials, such aslecithin, by the maintenance of the required particle size in the caseof dispersions, and by the use of surfactants.

These compositions can also contain adjuvants such as preservatives,wetting agents, emulsifying agents, dispersing agents, lubricants,and/or antioxidants. Prevention of the action of microorganisms upon thecompounds described herein can be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. In some embodiments,compositions disclosed herein include isotonic agents, such as sugars,sodium chloride, and the like into the compositions. In addition,prolonged absorption of the injectable pharmaceutical form can bebrought about by the inclusion of agents which delay absorption such asaluminum monostearate and gelatin.

Methods of preparing these formulations or compositions include the stepof bringing into association a compound described herein and/or thechemotherapeutic with the carrier and, optionally, one or more accessoryingredients. In general, the formulations are prepared by uniformly andintimately bringing into association a compound as disclosed herein withliquid carriers, or finely divided solid carriers, or both, and then, ifnecessary, shaping the product.

Preparations for such pharmaceutical compositions are well-known in theart. See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, WilliamG, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill,2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition,Churchill Livingston, N.Y., 1990; Katzung, cd., Basic and ClinicalPharmacology, Ninth Edition, McGraw Hill, 20037ybg; Goodman and Gilman,eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGrawHill, 2001; Remingtons Pharmaceutical Sciences, 20th Ed., LippincottWilliams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia,Thirty-Second Edition (The Pharmaceutical Press, London, 1999); all ofwhich are incorporated by reference herein in their entirety. Exceptinsofar as any conventional excipient medium is incompatible with thecompounds provided herein, such as by producing any undesirablebiological effect or otherwise interacting in a deleterious manner withany other component(s) of the pharmaceutically acceptable composition,the excipient's use is contemplated to be within the scope of thisdisclosure.

In some embodiments, the concentration of one or more of polymorph(s)provided herein in a composition provided herein is less than about100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%,about 30%, about 20%, about 19%, about 18%, about 17%, about 16%, about15%, about 14%, about 13%, about 12%, about 11%, about 10%, about 9%,about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%,about 1%, about 0.5%, about 0.4%, about 0.3%, about 0.2, about 0.1%,about 0.09%, about 0.08%, about 0.07%, about 0.06%, about 0.05%, about0.04%, about 0.03%, about 0.02%, about 0.01%, about 0.009%, about0.008%, about 0.007%, about 0.006%, about 0.005%, about 0.004%, about0.003%, about 0.002%, about 0.001%, about 0.0009%, about 0.0008%, about0.0007%, about 0.0006%, about 0.0005%, about 0.0004%, about 0.0003%,about 0.0002%, or about 0.0001% w/w, w/v, or v/v.

In some embodiments, the concentration of one or more of polymorph(s)provided herein in a composition provided herein is greater than about90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%,about 20%, about 19.75%, about 19.50%, about 19.25%, about 19%, about18.75%, about 18.50%, about 18.25%, about 18%, about 17.75%, about17.50%, about 17.25%, about 17%, about 16.75%, about 16.50%, about16.25%, about 16%, about 15.75%, about 15.50%, about 15.25%, about 15%,about 14.75%, about 14.50%, about 14.25%, about 14%, about 13.75%, about13.50%, about 13.25%, about 13%, about 12.75%, about 12.50%, about12.25%, about 12%, about 11.75%, about 11.50%, about 11.25%, about 11%,about 10.75%, about 10.50%, about 10.25%, about 10%, about 9.75%, about9.50%, about 9.25%, about 9%, about 8.75%, about 8.50%, about 8.25%,about 8%, about 7.75%, about 7.50%, about 7.25%, about 7%, about 6.75%,about 6.50%, about 6.25%, about 6%, about 5.75%, about 5.50%, about5.25%, about 5%, about 4.75%, about 4.50%, about 4.25%, about 4%, about3.75/6, about 3.50%, about 3.25%, about 3%, about 2.75%, about 2.50%,about 20.25%, about 2%, about 1.75%, about 1.50%, about 1.25%, about 1%,about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%, about 0.09%,about 0.08%, about 0.07%, about 0.06%, about 0.05%, about 0.04%, about0.03%, about 0.02%, about 0.01%, about 0.009%, about 0.008%, about0.007%, about 0.006%, about 0.005%, about 0.004%, about 0.003%, about0.002%, about 0.001%, about 0.0009%, about 0.0008%, about 0.0007%, about0.0006%, about 0.0005%, about 0.0004%, about 0.0003%, about 0.0002%, orabout 0.0001% w/w, w/v, or v/v.

In some embodiments, the concentration of one or more of polymorph(s)provided herein in a composition provided herein is in a range fromapproximately 0.0001% to approximately 50%, from approximately 0.001% toapproximately 40%, from approximately 0.01% to approximately 30%, fromapproximately 0.02% to approximately 29%, from approximately 0.03% toapproximately 28%, from approximately 0.04% to approximately 27%, fromapproximately 0.05% to approximately 26%, from approximately 0.06% toapproximately 25%, from approximately 0.07% to approximately 24%, fromapproximately 0.08% to approximately 23%, from approximately 0.09% toapproximately 22%, from approximately 0.1% to approximately 21%, fromapproximately 0.2% to approximately 20%, from approximately 0.3% toapproximately 19%, from approximately 0.4% to approximately 18%, fromapproximately 0.5% to approximately 17%, from approximately 0.6% toapproximately 16%, from approximately 0.7% to approximately 15%, fromapproximately 0.8% to approximately 14%, from approximately 0.9% toapproximately 12%, from approximately 1% to approximately 10% w/w, w/v,or v/v.

In some embodiments, the concentration of one or more of polymorph(s)provided herein in a composition provided herein is in a range fromapproximately 0.001% to approximately 10%, from approximately 0.01% toapproximately 5%, from approximately 0.02% to approximately 4.5%, fromapproximately 0.03% to approximately 4%, from approximately 0.04% toapproximately 3.57, from approximately 0.05% to approximately 3%, fromapproximately 0.06% to approximately 2.5%, from approximately 0.07% toapproximately 2%, from approximately 0.08% to approximately 1.5%, fromapproximately 0.09% to approximately 1%, from approximately 0.1% toapproximately 0.9% w/w, w/v or v/v.

In some embodiments, the amount of one or more of polymorph(s) providedherein in a composition provided herein is equal to or less than about10 g, about 9.5 g, about 9.0 g, about 8.5 g, about 8.0 g, about 7.5 g,about 7.0 g, about 6.5 g, about 6.0 g, about 5.5 g, about 5.0 g, about4.5 g, about 4.0 g, about 3.5 g, about 3.0 g, about 2.5 g, about 2.0 g,about 1.5 g, about 1.0 g, about 0.95 g, about 0.9 g, about 0.85 g, about0.8 g, about 0.75 g, about 0.7 g, about 0.65 g, about 0.6 g, about 0.55g, about 0.5 g, about 0.45 g, about 0.4 g, about 0.35 g, about 0.3 g,about 0.25 g, about 0.2 g, about 0.15 g, about 0.1 g, about 0.09 g,about 0.08 g, about 0.07 g, about 0.06 g, about 0.05 g, about 0.04 g,about 0.03 g, about 0.02 g, about 0.01 g, about 0.009 g. about 0.008 g,about 0.007 g, about 0.006 g, about 0.005 g, about 0.004 g, about 0.003g, about 0.002 g, about 0.001 g, about 0.0009 g, about 0.0008 g, about0.0007 g. about 0.0006 g, about 0.0005 g, about 0.0004 g, about 0.0003g, about 0.0002 g, or about 0.0001 g.

In some embodiments, the amount of one or more of polymorph(s) providedherein in a composition provided herein is more than about 0.0001 g,about 0.0002 g, about 0.0003 g, about 0.0004 g, about 0.0005 g, about0.0006 g, about 0.0007 g, about 0.0008 g, about 0.0009 g, about 0.001 g,about 0.0015 g, about 0.002 g, about 0.0025 g, about 0.003 g, about0.0035 g, about 0.004 g, about 0.0045 g, about 0.005 g, about 0.0055 g,about 0.006 g, about 0.0065 g, about 0.007 g, about 0.0075 g, about0.008 g, about 0.0085 g, about 0.009 g, about 0.0095 g, about 0.01 g,about 0.015 g, about 0.02 g, about 0.025 g, about 0.03 g, about 0.035 g,about 0.04 g, about 0.045 g, about 0.05 g, about 0.055 g, about 0.06 g,about 0.065 g, about 0.07 g, about 0.075 g, about 0.08 g, about 0.085 g,about 0.09 g, about 0.095 g, about 0.1 g, about 0.15 g, about 0.2 g,about 0.25 g, about 0.3 g, about 0.35 g, about 0.4 g, about 0.45 g,about 0.5 g, about 0.55 g, about 0.6 g, about 0.65 g, about 0.7 g, about0.75 g, about 0.8 g, about 0.85 g, about 0.9 g, about 0.95 g, about 1 g,about 1.5 g, about 2 g, about 2.5 g, about 3 g, about 3.5 g, about 4 g,about 4.5 g, about 5 g, about 5.5 g, about 6 g, about 6.5 g, about 7 g,about 7.5 g, about 8 g, about 8.5 g, about 9 g, about 9.5 g, about 10 g,or more.

In some embodiments, the amount of one or more of polymorph(s) providedherein in a composition provided herein is in a range of about 0.0001 toabout 10 g, about 0.0005 to about 9 g, about 0.001 to about 8 g, about0.005 to about 7 g, about 0.01 to about 6 g about, 0.05 to about 5 g,about 0.1 to about 4 g, about 0.5 to about 4 g, or about 1 to about 3 g.

In one embodiment, the polymorphs provided herein are effective over awide dosage range. For example, in the treatment of adult humans,dosages from about 0.01 to about 1000 mg, from about 0.5 to about 100mg, from about 1 to about 50 mg, and from about 5 to about 40 mg per dayare examples of dosages that can be used. An exemplary dosage is about10 to about 30 mg per day. The exact dosage will depend upon the routeof administration, the form in which a polymorph is administered, thesubject to be treated, the body weight of the subject to be treated, andthe preference and experience of the attending physician.

Described below are non-limiting exemplary pharmaceutical compositionsand methods for preparing the same.

Pharmaceutical Compositions for Oral Administration:

In some embodiments, provided herein is a pharmaceutical composition fororal administration, wherein the composition comprises a polymorphprovided herein or a pharmaceutically acceptable form (e.g.,pharmaceutically acceptable salts, hydrates, solvates, chelates,non-covalent complexes, isomers, prodrugs, and isotopically labeledderivatives) thereof, and a pharmaceutically acceptable excipient (e.g.,an excipient suitable for oral administration).

In one embodiment, the composition provided herein is a solid dosageform comprising a polymorph of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or hydrate thereof, and oneor more pharmaceutically acceptable excipients. In one embodiment, thecomposition provided herein is a single unit dosage form comprising apolymorph of a compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, or hydrate thereof. In one embodiment, the compositionprovided herein is a tablet or a capsule. In one embodiment, thecomposition provided herein comprises a therapeutically effective amountof a polymorph of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or hydrate thereof.

In one embodiment, the composition provided herein comprises atherapeutically effective amount of a polymorph of a compound of Formula(I), or a pharmaceutically acceptable salt, solvate, or hydrate thereof.In some embodiments, the therapeutically effective amount is about 0.5,about 1, about 2, about 3, about 4, about 5, about 10, about 15, about20, about 25, about 30, about 35, about 40, about 45, about 50, about55, about 60, about 65, about 70, about 75, about 80, about 85, about90, about 95, about 100, about 110, about 120, about 130, about 140,about 150, about 160, about 170, about 180, about 190, about 200, about210, about 220, about 230, about 240, about 250, about 260, about 270,about 280, about 290, about 300, about 325, about 350, about 375, about400, about 425, about 450, about 475, about 500, about 600, about 700,about 800, about 900, or about 1000 mg, or more. In one embodiment, thecomposition provided herein comprises at least one pharmaceuticallyacceptable carrier or excipient. In some embodiments, the compositionprovided herein comprises one or more pharmaceutically acceptablecarrier(s) or excipient(s), including, e.g., microcrystalline cellulose,crospovidone, and/or magnesium stearate. In one embodiment, thecomposition provided herein is an immediate-release dosage form. In someembodiments, the composition provided herein is a hard gelatin capsule.In some embodiments, the composition provided herein is a soft gelatincapsule. In some embodiments, the composition provided herein comprisesForm C of a compound of Formula (I). In some embodiments, thecomposition provided herein comprises Form A of a compound of Formula(I). In some embodiments, the composition provided herein comprises anamorphous form of a compound of Formula (I). In some embodiments, thecomposition provided herein comprises a mixture of two or morepolymorphs of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or hydrate thereof, e.g., polymorphs describedherein.

In other embodiments, the composition provided herein includes one ormore compounds of Formula (I) and is a suspension comprisingcarboxymethyl cellulose and water. In one embodiment, the compositionprovided herein can further comprise one or mom excipients, such as,e.g., polysorbate, polyethyleneglycol, cyclodextrin, dextrose,n-methylpyrrolidone, pH buffers, dilute hydrochloric acid,polyoxyethylene esters of 12-hydroxystearic acid, or a mixture of two ormore thereof. In one embodiment, the process for preparing thesuspension includes, but is not limited to, combining a pre-determinedamount of a compound of Formula (I) in powder form with a vehicle, suchas commercially available medium viscosity USP carboxymethylcellulosesodium (CMC) in Sterile Water for Injection (SWFI).

In some embodiments, provided herein is a solid pharmaceuticalcomposition suitable for oral administration, comprising: (i) aneffective amount of a compound provided herein or a pharmaceuticallyacceptable form (e.g., pharmaceutically acceptable salts, hydrates,solvates, chelates, non-covalent complexes, isomers, prodrugs, andisotopically labeled derivatives) thereof; optionally (ii) an effectiveamount of a second agent; and (iii) one or more pharmaceuticalexcipients suitable for oral administration. In some embodiments, thecomposition further contains: (iv) an effective amount of a third agent.

In some embodiments, provided herein is a liquid pharmaceuticalcomposition suitable for oral administration. In some embodiments,provided herein is a capsule dosage form suitable for oraladministration.

In certain embodiments, pharmaceutical compositions provided hereinsuitable for oral administration can be presented as discrete dosageforms, such as capsules, pills, cachets, or tablets, or liquids oraerosol sprays each containing a predetermined amount of an activeingredient as a powder or in granules, a solution, or a suspension in anaqueous or non-aqueous liquid, an oil-in-water emulsion, or awater-in-oil liquid emulsion. In general, for solid forms, thecompositions are prepared by uniformly and intimately admixing theactive ingredient with liquid carriers or finely divided solid carriersor both, and then, if necessary, shaping the product into a certainpresentation. For example, a tablet can be prepared by compression ormolding, optionally with one or more accessory ingredients. Compressedtablets can be prepared by compressing in a suitable machine the activeingredient in a free-flowing form such as powder or granules, optionallymixed with an excipient such as, but not limited to, a binder, alubricant, an inert diluent, and/or a surface active or dispersingagent. Molded tablets can be made by molding in a suitable machine amixture of the powdered compound moistened with an inert liquid orsemi-solid diluent.

Solid compositions of a similar type can be employed as fillers in softand hard-filled gelatin capsules using such excipients as lactose ormilk sugar as well as high molecular weight polyethylene glycols and thelike. The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They can optionally comprise opacifying agents and can be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes. Solid compositions of asimilar type can be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polyethylene glycols and the like.

The active ingredients can be in micro-encapsulated form and canoptionally contain one or more excipients as noted above. The soliddosage forms of tablets, dragees, capsules, pills, and granules can beprepared with coatings and shells such as enteric coatings, releasecontrolling coatings and other coatings well known in the pharmaceuticalformulating art. In such solid dosage forms the active ingredient can beadmixed with at least one inert diluent such as sucrose, lactose orstarch. Such dosage forms can comprise, as is normal practice,additional substances other than inert diluents, e.g., tabletinglubricants and other tableting aids such a magnesium stearate andmicrocrystalline cellulose. In the case of capsules, tablets and pills,the dosage forms can comprise buffering agents. They can optionallycomprise opacifying agents and can be of a composition that they releasethe active ingredient(s) only, or preferentially, in a certain part ofthe intestinal tract, optionally, in a delayed manner. Examples ofembedding compositions which can be used include polymeric substancesand waxes.

Also provided herein are anhydrous pharmaceutical compositions anddosage forms comprising an active ingredient, since water can facilitatethe degradation of some compounds. For example, water can be added(e.g., 5%) in the pharmaceutical arts as a means of simulating long-termstorage in order to determine characteristics such as shelf-life or thestability of formulations over time. Anhydrous pharmaceuticalcompositions and dosage forms provided herein can be prepared usinganhydrous or low moisture containing ingredients and low moisture or lowhumidity conditions. Pharmaceutical compositions and dosage formsprovided herein which contain lactose can be made anhydrous ifsubstantial contact with moisture and/or humidity during manufacturing,packaging, and/or storage is expected. An anhydrous pharmaceuticalcomposition can be prepared and stored such that its anhydrous nature ismaintained. Accordingly, anhydrous compositions can be packaged usingmaterials known to prevent exposure to water such that they can beincluded in suitable formulary kits. Examples of suitable packaginginclude, but are not limited to, hermetically sealed foils, plastic orthe like, unit dose containers, blister packs, and strip packs.

In certain embodiments, an active ingredient can be combined in anintimate admixture with a pharmaceutical carrier according toconventional pharmaceutical compounding techniques. The carrier can takea wide variety of forms depending on the form of preparation intendedfor administration. In preparing the compositions for an oral dosageform, any of the usual pharmaceutical media can be employed as carriers,such as, for example, water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents, and the like in the case of oral liquidpreparations (such as suspensions, solutions, and elixirs) or aerosols;or carriers such as starches, sugars, micro-crystalline cellulose,diluents, granulating agents, lubricants, binders, and disintegratingagents can be used in the case of oral solid preparations, in someembodiments, without employing the use of lactose. For example, suitablecarriers include powders, capsules, and tablets, with solid oralpreparations. In some embodiments, tablets can be coated by standardaqueous or nonaqueous techniques.

In one embodiment, the active ingredient can optionally be mixed withone or more inert, pharmaceutically acceptable excipient or carrier suchas sodium citrate or dicalcium phosphate and/or a) fillers or extenderssuch as starches, lactose, sucrose, glucose, mannitol, and silicic acid,b) binders such as, for example, carboxymethylcellulose, alginates,gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants suchas glycerol, d) disintegrating agents such as agar, calcium carbonate,potato or tapioca starch, alginic acid, certain silicates, and sodiumcarbonate, e) solution retarding agents such as paraffin, f) absorptionaccelerators such as quaternary ammonium compounds, g) wetting agentssuch as, for example, cetyl alcohol and glycerol monostearate, h)absorbents such as kaolin and bentonite clay, and i) lubricants such astalc, calcium stearate, magnesium stearate, solid polyethylene glycols,sodium lauryl sulfate, and mixtures thereof. In the case of capsules,tablets and pills, the dosage form can comprise buffering agents.

In certain embodiments, binders suitable for use in pharmaceuticalcompositions and dosage forms include, but are not limited to, cornstarch, potato starch, or other starches, gelatin, natural and syntheticgums such as acacia, sodium alginate, alginic acid, other alginates,powdered tragacanth, guar gum, cellulose and its derivatives (e.g.,ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium,sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methylcellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose,microcrystalline cellulose, and mixtures of two or more thereof. In someembodiments, exemplary binding agents include, but are not limited to,starch (e.g. cornstarch and starch paste); gelatin; sugars (e.g.sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol,mannitol, etc.); natural and synthetic gums (e.g. acacia, sodiumalginate, extract of Irish moss, panwar gum, ghatti gum, mucilage ofisapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose,hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, cellulose acetate,poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and larcharabogalactan); alginates; polyethylene oxide; polyethylene glycol;inorganic calcium salts; silicic acid; polymethacrylates; waxes; water,alcohol; etc.; and mixtures of two or more thereof.

Examples of suitable fillers for use in the pharmaceutical compositionsand dosage forms disclosed herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures of two ormore thereof.

In certain embodiments, disintegrants can be used in the compositionsprovided herein to provide tablets that disintegrate when exposed to anaqueous environment. Too much of a disintegrant can produce tabletswhich can disintegrate in the bottle. Too little can be insufficient fordisintegration to occur and can thus alter the rate and extent ofrelease of the active ingredient(s) from the dosage form. Thus, asufficient amount of disintegrant that is neither too little nor toomuch to detrimentally alter the release of the active ingredient(s) canbe used to form the dosage forms of the polymorphs disclosed herein. Theamount of disintegrant used can vary based upon the type of formulationand mode of administration. In certain embodiments, about 0.5 to about15 weight percent of disintegrant, or about 1 to about 5 weight percentof disintegrant, can be used in a pharmaceutical composition providedherein. Disintegrants that can be used to form pharmaceuticalcompositions and dosage forms provided herein include, but are notlimited to, agar-agar, alginic acid, calcium carbonate, microcrystallinecellulose, croscarmellose sodium, crospovidone, polacrilin potassium,sodium starch glycolate, potato or tapioca starch, pre-gelatinizedstarch, other starches, clays, other algins, other celluloses, gums, andmixtures of two or more thereof.

In certain embodiments, lubricants which can be used to formpharmaceutical compositions and dosage forms provided herein include,but are not limited to, calcium stearate, magnesium stearate, mineraloil, light mineral oil, glycerin, glyceryl behanate, sorbitol, mannitol,polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate,sodium benzoate, sodium acetate, sodium chloride, leucine, magnesiumlauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil,cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethylaureate, agar, malt, andmixtures of two or more thereof. Additional lubricants include, forexample, a syloid silica gel, a coagulated aerosol of synthetic silica,or mixtures of two or more thereof. In certain embodiments, a lubricantcan optionally be added, in an amount of less than about 1 weightpercent of the pharmaceutical composition.

In some embodiments, a pharmaceutical composition or dosage formprovided herein comprises colloid particle(s). In some cases, colloidparticles include at least one cationic agent and at least one non-ionicsurfactant, such as a poloxamer, tyloxapol, a polysorbate, apolyoxyethylene castor oil derivative, a sorbitan ester, or a polyoxylstearate. In some cases, the cationic agent is an alkylamine, a tertiaryalkyl amine, a quatemary ammonium compound, a cationic lipid, an aminoalcohol, a biguanidine salt, a cationic compound, or a mixture of two ormore thereof. In some cases, the cationic agent is a biguanidine salt,such as chlorhexidine, polyaminopropyl biguanidine, phenformin,alkylbiguanidine, or a mixture of two or more thereof. In some cases,the quaternary ammonium Formula (I)s a benzalkonium halide, lauralkoniumhalide, cetrimide, hexadecyltrimethylammonium halide,tetradecyltrimethyl-ammonium halide, dodecyltrimethylammonium halide,cetrimonium halide, benzethonium halide, behenalkonium halide,cetalkonium halide, cetethyldimonium halide, cetylpyridinium halide,benzododecinium halide, chlorallyl methenamine halide, myristylalkoniumhalide, stearalkonium halide, or a mixture of two or more thereof. Insome cases, cationic agent is a benzalkonium chloride, lauralkoniumchloride, benzododecinium bromide, benzethenium chloride,hexadecyltrimethylammonium bromide, tetradecyltrimethylammonium bromide,dodecyltrimethylammonium bromide, or a mixture of two or more thereof.In some cases, colloid particles comprise an oil phase. In some cases,the oil phase is mineral oil, light mineral oil, medium chaintriglycerides (MCT), coconut oil, hydrogenated oils comprisinghydrogenated cottonseed oil, hydrogenated palm oil, hydrogenate castoroil, hydrogenated soybean oil, polyoxyethylene hydrogenated castor oilderivatives comprising poluoxyl-40 hydrogenated castor oil, polyoxyl-60hydrogenated castor oil, or polyoxyl-100 hydrogenated castor oil.

In one embodiment, when aqueous suspensions and/or elixirs are intendedfor oral administration, the active ingredient therein can be combinedwith various sweetening or flavoring agents, coloring matter or dyesand, in some embodiments, emulsifying and/or suspending agents, togetherwith such diluents as water, ethanol, propylene glycol, glycerin, andvarious combinations thereof.

In certain embodiments, tablets can be uncoated or coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material, such as glycerylmonostearate or glyceryl distearate, can be employed, Formulations fororal use can also be presented as hard gelatin capsules, wherein theactive ingredient is mixed with an inert solid diluent, for example,calcium carbonate, calcium phosphate, or kaolin; or as soft gelatincapsules, wherein the active ingredient is mixed with water or an oilmedium, for example, peanut oil, liquid paraffin, or olive oil.

In certain embodiments, surfactants which can be used to formpharmaceutical compositions and dosage forms provided herein include,but are not limited to, hydrophilic surfactants, lipophilic surfactants,and mixtures of two or more thereof. For example, a mixture ofhydrophilic surfactants can be employed, a mixture of lipophilicsurfactants can be employed, or a mixture of at least one hydrophilicsurfactant and at least one lipophilic surfactant can be employed.

In certain embodiments, a suitable hydrophilic surfactant can generallyhave an HLB value of at least 10, while suitable lipophilic surfactantscan generally have an HLB value of or less than about 10. An empiricalparameter used to characterize the relative hydrophilicity andhydrophobicity of non-ionic amphiphilic compounds is thehydrophilic-lipophilic balance (“HLB” value). Surfactants with lower HLBvalues are more lipophilic or hydrophobic, and have greater solubilityin oils, while surfactants with higher HLB values are more hydrophilic,and have greater solubility in aqueous solutions. Hydrophilicsurfactants are generally considered to be those compounds having an HLBvalue greater than about 10, as well as anionic, cationic, orzwitterionic compounds for which the HLB scale is not generallyapplicable. Similarly, lipophilic (i.e., hydrophobic) surfactants arecompounds having an HLB value equal to or less than about 10. However,HLB value of a surfactant is merely a rough guide generally used toenable formulation of industrial, pharmaceutical, and cosmeticemulsions.

In certain embodiments, hydrophilic surfactants can be either ionic ornon-ionic. Suitable ionic surfactants include, but are not limited to,alkylammonium salts; fusidic acid salts; fatty acid derivatives of aminoacids, oligopeptides, and polypeptides; glyceride derivatives of aminoacids, oligopeptides, and polypeptides; lecithins and hydrogenatedlecithins; lysolecithins and hydrogenated lysolecithins; phospholipidsand derivatives thereof; lysophospholipids and derivatives thereof;carnitine fatty acid ester salts; salts of alkylsulfates; fatty acidsalts; sodium docusate; acylactylates; mono- and di-acetylated tartaricacid esters of mono- and di-glycerides; succinylated mono- anddi-glycerides; citric acid esters of mono- and di-glycerides; andmixtures of two or more thereof.

Within the aforementioned group, ionic surfactants include, by way ofexample: lecithins, lysolecithin, phospholipids, lysophospholipids andderivatives thereof; carnitine fatty acid ester salts; salts ofalkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono-and di-acetylated tartaric acid esters of mono- and di-glycerides;succinylated mono- and di-glycerides; citric acid esters of mono- anddi-glycerides; and mixtures of two or more thereof.

In certain embodiments, ionic surfactants can be ionized forms oflecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine,phosphatidylglycerol, phosphatidic acid, phosphatidylserine,lysophosphatidylcholine, lysophosphatidylethanolamine,lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine,PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactylicesters of fatty acids, stearoyl-2-lactylate, stearyl lactylate,succinylated monoglycerides, mono/diacetylated tartaric acid esters ofmono/diglycerides, citric acid esters of mono/diglycerides,cholylsarcosine, caproate, caprylate, caprate, laurate, myristate,palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, laurylsulfate, teracecyl sulfate, docusate, lauroyl carnitines, palmitoylcamitines, myristoyl camitines, salts thereof, and mixtures of two ormore thereof.

In certain embodiments, hydrophilic non-ionic surfactants can include,but are not limited to, alkylglucosides; alkylmaltosides;alkylthioglucosides; lauryl macrogolglycerides; polyoxyalkylene alkylethers such as polyethylene glycol alkyl ethers; polyoxyalkylenealkylphenols such as polyethylene glycol alkyl phenols; polyoxyalkylenealkyl phenol fatty acid esters such as polyethylene glycol fatty acidsmonoesters and polyethylene glycol fatty acids diesters; polyethyleneglycol glycerol fatty acid esters; polyglycerol fatty acid esters:polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycolsorbitan fatty acid esters; hydrophilic transesterification products ofa polyol with at least one member of the group consisting of glycerides,vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols;polyoxyethylene sterols, derivatives, and analogues thereof,polyoxyethylated vitamins and derivatives thereof;polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof;polyethylene glycol sorbitan fatty acid esters and hydrophilictransesterification products of a polyol with at least one member of thegroup consisting of triglycerides, vegetable oils, hydrogenatedvegetable oils, and mixtures of two or more thereof. The polyol can beglycerol, ethylene glycol, polyethylene glycol, sorbitol, propyleneglycol, pentaerythritol, or a saccharide.

Other hydrophilic-non-ionic surfactants include, without limitation,PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate,PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate,PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryllaurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenatedcastor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides,polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitanlaurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearylether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglyceryl-10oleate, Tween® 40, Tween®860, sucrose monostearate, sucrose monolaurate,sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG 15-100 octylphenol series, and poloxamers, and mixtures of two or more thereof.

In certain embodiments, suitable lipophilic surfactants include, by wayof example only: fatty alcohols; glycerol fatty acid esters; acetylatedglycerol fatty acid esters; lower alcohol fatty acids esters; propyleneglycol fatty acid esters; sorbitan fatty acid esters; polyethyleneglycol sorbitan fatty acid esters; sterols and sterol derivatives;polyoxyethylated sterols and sterol derivatives; polyethylene glycolalkyl ethers; sugar esters; sugar ethers; lactic acid derivatives ofmono- and di-glycerides; hydrophobic transesterification products of apolyol with at least one member of the group consisting of glycerides,vegetable oils, hydrogenated vegetable oils, fatty acids and sterols;oil-soluble vitamins/vitamin derivatives; and mixtures of two or morethereof. Within this group, lipophilic surfactants include glycerolfatty acid esters, propylene glycol fatty acid esters, and mixtures oftwo more thereof; or include hydrophobic transesterification products ofa polyol with at least one member of the group consisting of vegetableoils, hydrogenated vegetable oils, and triglycerides.

In one embodiment, the pharmaceutical composition can include asolubilizer to ensure good solubilization and/or dissolution of acompound provided herein and/or to minimize precipitation of a compoundprovided herein. This can be useful for compositions for non-oral use,e.g., compositions for injection. A solubilizer can also be added toincrease the solubility of a hydrophilic drug and/or other components,such as surfactants, or to maintain the composition as a stable orhomogeneous solution or dispersion.

Examples of suitable solubilizers include, but ae not limited to, thefollowing: alcohols and polyols, such as ethanol, isopropyl alcohol,butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediolsand isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol,transcutol, dimethyl isosorbide, polyethylene glycol, polypropyleneglycol, polyvinylalcohol, hydroxypropyl methylcellulose and othercellulose derivatives, cyclodextrins and cyclodextrin derivatives;ethers of polyethylene glycols having an average molecular weight ofabout 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether(glycofurol) or methoxy PEG; amides and other nitrogen-containingcompounds such as 2-pyrrolidone, 2-piperidone, ε-caprolactam,N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone,N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esterssuch as ethyl propionate, tributylcitrate, acetyl triethylcitrate,acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate,ethyl butyrate, triacetin, propylene glycol monoacetate, propyleneglycol diacetate, ε-caprolactone and isomers thereof, δ-valerolactoneand isomers thereof, β-butyrolactone and isomers thereof; and othersolubilizers known in the art, such as dimethyl acetamide, dimethylisosorbide, N-methyl pyrrolidones, monooctanoin, diethylene glycolmonoethyl ether, water, and mixtures of two or more thereof. In certainembodiments, a solubilizer comprising polyglycol mono- and di-esters of12-hydroxystearic acid and about 30% free polyethylene glycol (availableas Solutol® HS 15) is used as a solubilizer in a composition providedherein.

In certain embodiments, mixtures of solubilizers can be used. Examplesinclude, but not limited to, mixtures of two or more of triacetin,triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide,N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone,hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol,polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol,or dimethyl isosorbide. In certain embodiments, solubilizers includesorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol, andpropylene glycol.

In certain embodiments, the amount of solubilizer that can be includedis not particularly limited. The amount of a given solubilizer can belimited to a bioacceptable amount, which can be readily determined byone of skill in the art. In some circumstances, it can be advantageousto include amounts of solubilizers far in excess of bioacceptableamounts, for example to maximize the concentration of the drug, withexcess solubilizer removed prior to providing the composition to asubject using conventional techniques, such as distillation orevaporation. Thus, if present, the solubilizer can be in a weight ratioof about 10%, about 25%, about 50%, about 100%, or up to about 200% byweight, based on the combined weight of the drug, and other excipients.In some embodiments, very small amounts of solubilizer can also be used,such as about 5%, about 2%, about 1%, or even less. In certainembodiments, the solubilizer can be present in an amount of about 1% toabout 100%, or about 5% to about 25% by weight.

In one embodiment, a composition provided herein can further include oneor more pharmaceutically acceptable additives and/or excipients. Suchadditives and excipients include, without limitation, detackifiers,anti-foaming agents, buffering agents, polymers, antioxidants,preservatives, chelating agents, viscomodulators, tonicifiers,flavorants, colorants, odorants, opacifiers, suspending agents, binders,fillers, plasticizers, lubricants, and mixtures of two or more thereof.In another embodiment, a composition provided herein can further includeone or more pharmaceutically acceptable additives and/or excipients,such as, but not limited to, inert diluents, dispersing and/orgranulating agents, surface active agents and/or emulsifiers,disintegrating agents, binding agents, preservatives, buffering agents,lubricating agents, and/or oils. For example, excipients such as cocoabutter and suppository waxes, coloring agents, coating agents,sweetening, flavoring, and perfuming agents can be present in thecomposition.

Exemplary surface active agents and/or emulsifiers include, but are notlimited to, natural emulsifiers (e.g. acacia, agar, alginic acid, sodiumalginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin,egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidalclays (e.g. bentonite [aluminum silicate] and Veegum [magnesium aluminumsilicate]), long chain amino acid derivatives, high molecular weightalcohols (e.g. stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetinmonostearate, ethylene glycol distearate, glyceryl monostearate, andpropylene glycol monostearate, polyvinyl alcohol), carbomers (e.g.carboxy polymethylene, polyacrylic acid, acrylic acid polymer, andcarboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g.carboxymethylcellulose sodium, powdered cellulose, hydroxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,methylcellulose), sorbitan fatty acid esters (e.g. polyoxyethylenesorbitan monolaurate [Tween® 20], polyoxyethylene sorbitan [Tween® 60],polyoxyethylene sorbitan monooleate [Tween® 80], sorbitan monopalmitate[Span 40], sorbitan monostearate [Span 60], sorbitan tristearate [Span65], glyceryl monooleate, sorbitan monooleate [Span 80]),polyoxyethylene esters (e.g. polyoxyethylene monostearate [Myrj 45],polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil,polyoxymethylene stearate, and Solutol®), sucrose fatty acid esters,polyethylene glycol fatty acid esters (e.g. Cremophor®), polyoxyethyleneethers. (e.g. polyoxyethylene lauryl ether [Brij 30]),poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamineoleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyllaurate, sodium lauryl sulfate, Pluronic F 68, Poloxamer 188,cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride,docusate sodium, etc. and/or combinations thereof.

Exemplary preservatives can include antioxidants, chelating agents,antimicrobial preservatives, antifungal preservatives, alcoholpreservatives, acidic preservatives, and other preservatives. Exemplaryantioxidants include, but are not limited to, alpha tocopherol, ascorbicacid, acorbyl palmitate, butylated hydroxyanisole, butylatedhydroxytoluene, monothioglycerol, potassium metabisulfite, propionicacid, propyl gallate, sodium ascorbate, sodium bisulfite, sodiummetabisulfite, and sodium sulfite. Exemplary chelating agents includeethylenediaminetetraacetic acid (EDTA), citric acid monohydrate,disodium edetate, dipotassium edetate, edetic acid, fumaric acid, malicacid, phosphoric acid, sodium edetate, tartaric acid, and trisodiumedetate. Exemplary antimicrobial preservatives include, but are notlimited to, benzalkonium chloride, benzethonium chloride, benzylalcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine,chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol,glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethylalcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.Exemplary antifungal preservatives include, but are not limited to,butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoicacid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodiumbenzoate, sodium propionate, and sorbic acid. Exemplary alcoholpreservatives include, but are not limited to, ethanol, polyethyleneglycol, phenol, phenolic compounds, bisphenol, chlorobutanol,hydroxybenzoate, and phenylethyl alcohol. Exemplary acidic preservativesinclude, but are not limited to, vitamin A, vitamin C, vitamin E,beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbicacid, sorbic acid, and phytic acid. Other preservatives include, but arenot limited to, tocopherol, tocopherol acetate, deteroxime mesylate,cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened(BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ethersulfate (SLES), sodium bisulfite, sodium metabisulfite, potassiumsulfite, potassium metabisulfite, Glydant® Plus, Phenonip,methylparaben, Germall® 115, Germaben® 11, Ncolonc™, Kathon™, andEuxyl®. In certain embodiments, the preservative is an anti-oxidant. Inother embodiments, the preservative is a chelating agent.

Exemplary oils include, but are not limited to, almond, apricot kernel,avocado, babassu, bergamot, black current seed, borage, cade, camomile,canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, codliver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose,fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop,isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon,litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink,nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel,peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary,safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, sheabutter, silicone, soybean, sunflower, tea tree, thistle, tsubaki,vetiver, walnut, and wheat germ oils. Exemplary oils include, but arenot limited to, butyl stearate, caprylic triglyceride, caprictriglyceride, cyclomethicone, diethyl sebacate, dimethicone 360,isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol,silicone oil, and combinations thereof.

Exemplary granulating and/or dispersing agents include, but are notlimited to, potato starch, corn starch, tapioca starch, sodium starchglycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite,cellulose and wood products, natural sponge, cation-exchange resins,calcium carbonate, silicates, sodium carbonate, cross-linkedpoly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch(sodium starch glycolate), carboxymethyl cellulose, cross-linked sodiumcarboxymethyl cellulose (croscarmellose), methylcellulose,pregelatinized starch (starch 1500), microcrystalline starch, waterinsoluble starch, calcium carboxymethyl cellulose, magnesium aluminumsilicate (Veegum®), sodium lauryl sulfate, quaternary ammoniumcompounds, etc., and combinations thereof.

Exemplary diluents include, but are not limited to, calcium carbonate,sodium carbonate, calcium phosphate, dicalcium phosphate, calciumsulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose,cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol,inositol, sodium chloride, dry starch, cornstarch, powdered sugar, etc.,and combinations thereof.

In another embodiment, an acid or a base can be incorporated into acomposition provided herein to facilitate processing, to enhancestability, or for other reasons. Examples of pharmaceutically acceptablebases include, but am not limited to, amino acids, amino acid esters,ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodiumhydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesiumhydroxide, magnesium aluminum silicate, synthetic aluminum silicate,synthetic hydrocalcite, magnesium aluminum hydroxide,diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine,triethylamine, triisopropanolamine, trimethylamine,tris(hydroxymethyl)aminomethane (TRIS), and the like. In certainembodiments, pharmaceutically acceptable bases are salts of apharmaceutically acceptable acid. Examples of pharmaceuticallyacceptable acids include, but are not limited to, acetic acid, acrylicacid, adipic acid, alginic acid, alkanesulfonic acid, amino acids,ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid,citric acid, fatty acids, formic acid, fumaric acid, gluconic acid,hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid,oxalic acid, para-bromophenylsulfonic acid, propionic acid,p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid,tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid,uric acid, and the like; and salts of polyprotic acids, such as sodiumphosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate.When the base is a salt, the cation can be any convenient andpharmaceutically acceptable cation, such as ammonium, alkali metals,alkaline earth metals, and the like. Example can include, but notlimited to, sodium, potassium, lithium, magnesium, calcium and ammonium.

In one embodiment, suitable acids are pharmaceutically acceptableorganic or inorganic acids. Examples of suitable inorganic acidsinclude, but are not limited to, hydrochloric acid, hydrobromic acid,hydriodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid,and the like. Examples of suitable organic acids include, but are notlimited to, acetic acid, acrylic acid, adipic acid, alginic acid,alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boricacid, butyric acid, carbonic acid, citric acid, fatty acids, formicacid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbicacid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid,para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid,salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid,thioglycolic acid, toluenesulfonic acid, uric acid, and the like.

Pharmaceutical Compositions for Parenteral Administration:

In some embodiments, provided herein are pharmaceutical compositions forparenteral administration containing a polymorph provided herein or apharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, chelates, non-covalent complexes, isomers,prodrugs, and isotopically labeled derivatives) thereof, and apharmaceutical excipient suitable for parenteral administration. In someembodiments, provided herein are pharmaceutical compositions forparenteral administration containing: (i) an effective amount of adisclosed compound or a pharmaceutically acceptable form (e.g.,pharmaceutically acceptable salts, hydrates, solvates, chelates,non-covalent complexes, isomers, prodrugs, and isotopically labeledderivatives) thereof; optionally (ii) an effective amount of one or moresecond agents; and (iii) one or more pharmaceutical excipients suitablefor parenteral administration. In some embodiments, the pharmaceuticalcomposition further contains: (iv) an effective amount of a third agent.

In certain embodiments, the forms in which a composition provided hereincan be incorporated for administration by injection include aqueous oroil suspensions, or emulsions, with sesame oil, corn oil, cottonseedoil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterileaqueous solution, and similar pharmaceutical vehicles.

Liquid dosage forms for oral and parenteral administration include, butare not limited to, pharmaceutically acceptable emulsions,microemulsions, solutions, suspensions, syrups and elixirs. In additionto the active ingredients, the liquid dosage forms can comprise inertdiluents commonly used in the art such as, for example, water or othersolvents, solubilizing agents and emulsifiers such as ethyl alcohol,isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol,benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethylformamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan, andmixtures thereof. In certain embodiments for parenteral administration,the compounds disclosed herein can be mixed with solubilizing agentssuch as Cremophor®, alcohols, oils, modified oils, glycols,polysorbates, cyclodextrins, polymers, and combinations thereof.

In certain embodiments, aqueous solutions in saline are used forinjection. In certain embodiments, ethanol, glycerol, propylene glycol,liquid polyethylene glycol, or the like (and suitable mixtures thereof),cyclodextrin derivatives, or vegetable oils can be employed. The sterileinjectable preparation can be a sterile injectable solution, suspensionor emulsion in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the exemplaryvehicles and solvents that can be employed are water, Ringer's solution,U.S.P. and isotonic sodium chloride solution. In addition, sterile,fixed oils are conventionally employed as a solvent or suspendingmedium. For this purpose, any bland fixed oil can be employed includingsynthetic mono- or diglycerides. In addition, fatty acids such as oleicacid am used in the preparation of injectables. The proper fluidity canbe maintained, for example, by the use of a coating, such as lecithin,for the maintenance of a certain particle size in the case of dispersionor by the use of surfactants. In certain embodiments, the prevention ofthe action of microorganisms can be brought about by variousantibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

In certain embodiments, sterile injectable solutions are prepared byincorporating a compound provided herein in a certain amount in anappropriate solvent with various other ingredients as enumerated herein,followed by filtration sterilization. In certain embodiments,dispersions are prepared by incorporating various sterilized activeingredients into a sterile vehicle which contains a basic dispersionmedium and various other ingredients as enumerated herein. In the caseof sterile powders for the preparation of sterile injectable solutions,suitable methods of preparation include, but are not limited to,vacuum-drying and freeze-drying techniques, which yield a powder of theactive ingredient plus any additional ingredient from a previouslysterile-filtered solution thereof.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use. Injectable compositions can contain from about 0.1to about 5% w/w of a compound as disclosed herein.

Pharmaceutical Compositions for Topical Administration:

In some embodiments, provided herein is a pharmaceutical composition fortopical (e.g., transdermal) delivery comprising a polymorph providedherein or a pharmaceutically acceptable form (e.g., pharmaceuticallyacceptable salts, hydrates, solvates, chelates, non-covalent complexes,isomers, prodrugs, and isotopically labeled derivatives) thereof and apharmaceutical excipient suitable for topical (e.g., transdermal)delivery. In some embodiments, provided herein are pharmaceuticalcompositions for topical administration containing: (i) an effectiveamount of a disclosed compound; optionally (ii) an effective amount ofone or more second agents; and (iii) one or more pharmaceuticalexcipients suitable for topical administration. In some embodiments, thepharmaceutical composition further contains: (iv) an effective amount ofa third agent.

In certain embodiments, compositions provided herein can be formulatedinto preparations in solid, semi-solid, or liquid forms suitable forlocal and/or topical administration, such as, e.g., gels, water solublejellies, creams, lotions, suspensions, foams, powders, slurries,ointments, solutions, oils, pastes, suppositories, sprays, emulsions,saline solutions, and dimethylsulfoxide (DMSO)-based solutions. In oneembodiment, carriers with higher densities are capable of providing anarea with a prolonged exposure to an active ingredient. By contrast, asolution formulation can provide more immediate exposure of an activeingredient to the chosen area.

In some embodiments, the pharmaceutical compositions can also comprisesuitable solid or gel phase carriers or excipients, which are compoundsthat allow increased penetration of or assist in the delivery of,therapeutic molecules across the stratum corneum permeability barrier ofthe skin. There are many of these penetration-enhancing molecules knownto those trained in the art of topical formulation. Examples of suchcarriers and excipients include, but are not limited to, humectants(e.g., urea), glycols (e.g., propylene glycol), alcohols (e.g.,ethanol), fatty acids (e.g., oleic acid), surfactants (e.g., isopropylmyristate and sodium lauryl sulfate), pyrrolidones, glycerolmonolaurate, sulfoxides, terpenes (e.g., menthol), amines, amides,alkanes, alkanols, water, calcium carbonate, calcium phosphate, varioussugars, starches, cellulose derivatives, gelatin, and polymers such aspolyethylene glycols.

In another embodiment, a pharmaceutical composition or dosage form foruse in a method provided herein employs transdermal delivery devices(“patches”). Such transdermal patches can be used to provide continuousor discontinuous infusion of a compound provided herein in controlledamounts, either with or without another agent.

The construction and use of transdermal patches for the delivery ofpharmaceutical agents is known in the art. See. e.g., U.S. Pat. Nos.5,023,252, 4,992,445 and 5,001,139, incorporated herein by reference.Such patches can be constructed for continuous, pulsatile, or on demanddelivery of pharmaceutical agents.

Suitable devices for use in delivering intradermal pharmaceuticallyacceptable compositions described herein include short needle devicessuch as those described in U.S. Pat. Nos. 4,886,499; 5,190,521;5,328,483; 5,527,288; 4,270,537; 5,015,235; 5,141,496; and 5,417,662.Intradermal compositions can be administered by devices which limit theeffective penetration length of a needle into the skin, such as thosedescribed in PCT publication WO 99/34850 and functional equivalentsthereof. Jet injection devices which deliver liquid vaccines to thedermis via a liquid jet injector and/or via a needle which pierces thestratum corneum and produces a jet which reaches the dermis aresuitable. Jet injection devices are described, for example, in U.S. Pat.Nos. 5,480,381; 5,599,302; 5,334,144; 5,993,412; 5,649,912; 5,569,189;5,704,911; 5,383,851; 5,893,397; 5,466,220; 5,339,163; 5,312,335;5,503,627; 5,064,413; 5,520,639; 4,596,556; 4,790,824; 4,941,880;4,940,460; and PCT publications WO 97/37705 and WO 97/13537. Ballisticpowder/particle delivery devices which use compressed gas to acceleratevaccine in powder form through the outer layers of the skin to thedermis are suitable. Alternatively or additionally, conventionalsyringes can be used in the classical mantoux method of intradermaladministration.

Topically-administrable formulations can, for example, comprise fromabout 1% to about 10% (w/w) compound of formula (I), although theconcentration of the compound of formula (I) can be as high as thesolubility limit of the compound of formula (I) in the solvent. In someembodiments, topically-administrable formulations can, for example,comprise from about 1% to about 9/(w/w) compound of formula (I), such asfrom about 1% to about 8% (w/w), further such as from about 1% to about7% (w/w), further such as from about 1% to about 6% (w/w), further suchas from about 1% to about 5% (w/w), further such as from about 1% toabout 4% (w/w), further such as from about 1% to about 3% (w/w), andfurther such as from about 1% to about 2% (w/w) compound of formula (I),Formulations for topical administration can further comprise one or moreof the additional pharmaceutically acceptable excipients describedherein.

Pharmaceutical Compositions for Inhalation Administration:

In some embodiments, provided herein are pharmaceutical compositions forinhalation administration containing a polymorph provided herein or apharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, chelates, non-covalent complexes, isomers,prodrugs, and isotopically labeled derivatives) thereof, and apharmaceutical excipient suitable for topical administration. In someembodiments, provided herein are pharmaceutical compositions forinhalation administration containing: (i) an effective amount of adisclosed compound or a pharmaceutically acceptable form (e.g.,pharmaceutically acceptable salts, hydrates, solvates, chelates,non-covalent complexes, isomers, prodrugs, and isotopically labeledderivatives) thereof; optionally (ii) an effective amount of one or moresecond agents; and (iii) one or more pharmaceutical excipients suitablefor inhalation administration. In some embodiments, the pharmaceuticalcomposition further contains: (iv) an effective amount of a third agent.

In some embodiments, provided herein are compositions for inhalation orinsufflation, which can include solutions and suspensions inpharmaceutically acceptable, aqueous or organic solvents, or mixturesthereof; and suitable powders. The liquid or solid compositions cancontain suitable pharmaceutically acceptable excipients as describedherein. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local and/or systemic effect. Incertain embodiments, compositions in pharmaceutically acceptablesolvents can be nebulized by use of inert gases. Nebulized solutions canbe inhaled directly from the nebulizing device or the nebulizing devicecan be attached to a face mask tent, or intermittent positive pressurebreathing machine. In certain embodiments, solution, suspension, orpowder compositions can be administered, e.g., orally or nasally, fromdevices that deliver the formulation in an appropriate manner.

Pharmaceutical Composition for Ocular Administration:

In some embodiments, provided herein is a pharmaceutical composition fortreating ophthalmic disorders. In one embodiment, the composition isformulated for ocular administration and it contains an effective amountof a polymorph provided herein or a pharmaceutically acceptable form(e.g., pharmaceutically acceptable salts, hydrates, solvates, chelates,non-covalent complexes, isomers, prodrugs, and isotopically labeledderivatives) thereof provided herein and a pharmaceutical excipientsuitable for ocular administration. In certain embodiments,pharmaceutical compositions provided herein suitable for ocularadministration can be presented as discrete dosage forms, such as dropsor sprays each containing a predetermined amount of an active ingredientin a solution, or a suspension in an aqueous or non-aqueous liquid, anoil-in-water emulsion, or a water-in-oil liquid emulsion. Otheradministration forms include eye drops, intraocular injection,intravitreal injection, topically, or through the use of a drug elutingdevice, microcapsule, implant, or microfluidic device. In some cases,the compounds as disclosed herein are administered with a carrier orexcipient that increases the intraocular penetrance of the compound suchas an oil and water emulsion with colloid particles having an oily coresurrounded by an interfacial film.

In some cases, the colloid particles include at least one cationic agentand at least one non-ionic sufactant such as a poloxamer, tyloxapol, apolysorbate, a polyoxyethylene castor oil derivative, a sorbitan ester,or a polyoxyl stearate. In some cases, the cationic agent is analkylamine, a tertiary alkyl amine, a quarternary ammonium compound, acationic lipid, an amino alcohol, a biguanidine salt, a cationiccompound or a mixture thereof. In some cases the cationic agent is abiguanidine salt such as chlorhexidine, polyaminopropyl biguanidine,phenformin, alkylbiguanidine, or a mixture thereof. In some cases, thequaternary ammonium Formula (I)s a benzalkonium halide, lauralkoniumhalide, cetrimide, hexadecyltrimethylammonium halide,tetradecyltrimethylammonium halide, dodecyltrimethylammonium halide,cetrimonium halide, benzethonium halide, behenalkonium halide,cetalkonium halide, cetethyldimonium halide, cetylpyridinium halide,benzododecinium halide, chlorallyl methenamine halide, myristylalkoniumhalide, stearalkonium halide or a mixture of two or more thereof. Insome cases, cationic agent is a benzalkonium chloride, lauralkoniumchloride, benzododecinium bromide, benzethenium chloride,hexadecyltrimethylammonium bromide, tetradecyltrimethylammonium bromide,dodecyltrimethylammonium bromide or a mixture of two or more thereof. Insome cases, the oil phase is mineral oil and light mineral oil, mediumchain triglycerides (MCT), coconut oil; hydrogenated oils comprisinghydrogenated cottonseed oil, hydrogenated palm oil, hydrogenate castoroil or hydrogenated soybean oil; polyoxyethylene hydrogenated castor oilderivatives comprising poluoxyl-40 hydrogenated castor oil, polyoxyl-60hydrogenated castor oil or polyoxyl-100 hydrogenated castor oil.

It is contemplated that all local routes to the eye can be usedincluding topical, subconjunctival, periocular, retrobulbar, subtenon,intracameral, intravitreal, intraocular, subretinal, juxtascleral andsuprachoroidal administration. Systemic or parenteral administration canbe feasible including, but not limited to intravenous, subcutaneous, andoral delivery. An exemplary method of administration will beintravitreal or subtenon injection of solutions or suspensions, orintravitreal or subtenon placement of bioerodible or non-bioerodibledevices, or by topical ocular administration of solutions orsuspensions, or posterior juxtascleral administration of a gel or creamformulation.

In some embodiments, eye drops can be prepared by dissolving an activeingredient in a sterile aqueous solution, such as, e.g., physiologicalsaline or buffering solution; or by combining powder compositions to bedissolved before use. Other vehicles can be chosen, as is known in theart, including but not limited to: balance salt solution, salinesolution, water soluble polyethers such as polyethyene glycol,polyvinyls such as polyvinyl alcohol and povidone, cellulose derivativessuch as methylcellulose and hydroxypropyl methylcellulose, petroleumderivatives such as mineral oil and white petrolatum, animal fats suchas lanolin, polymers of acrylic acid such as carboxypolymethylene gel,vegetable fats such as peanut oil, polysaccharides such as dextrans,glycosaminoglycans such as sodium hyaluronate; and mixtures of two ormom thereof. In some embodiments, additives ordinarily used in the eyedrops can be added. Such additives include isotonizing agents (e.g.,sodium chloride), buffer agent (e.g., boric acid, sodium monohydrogenphosphate, sodium dihydrogen phosphate), preservatives (e.g.,benzalkonium chloride, benzethonium chloride, chlorobutanol), thickeners(e.g., saccharide such as lactose, mannitol, maltose; e.g., hyaluronicacid or its salt such as sodium hyaluronate, potassium hyaluronate;e.g., mucopolysaccharide such as chondroitin sulfate; e.g., sodiumpolyacrylate, carboxyvinyl polymer, crosslinked polyacrylate, polyvinylalcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxy propylmethylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose,hydroxy propyl cellulose, or other agents known to those skilled in theart).

Other Routes of Administration:

In one embodiment, the compositions provided herein can also bedelivered via an impregnated or coated device such as a stent, forexample, or an artery-inserted cylindrical polymer. Such a method ofadministration can, for example, aid in the prevention or ameliorationof restenosis following procedures such as balloon angioplasty. Withoutbeing bound by any particular theory, a compound provided herein canslow or inhibit the migration and proliferation of smooth muscle cellsin the arterial wall which contribute to restenosis. A compound providedherein can be administered, for example, by local delivery from thestruts of a stent, from a stent graft, from grafts, or from the cover orsheath of a stent. In some embodiments, a compound provided herein isadmixed with a matrix. Such a matrix can be a polymeric matrix, and canserve to bond the compound to the stent. Polymeric matrices suitable forsuch use, include, for example, lactone-based polyesters or copolyesterssuch as polylactide, polycaprolactonglycolide, polyorthoesters,polyanhydrides, polyaminoacids, polysaccharides, polyphosphazenes, poly(ether-ester) copolymers (e.g., PEO-PLLA); polydimethylsiloxane,poly(ethylene-vinylacetate), acrylate-based polymers or copolymers(e.g., polyhydroxyethyl methylmethacrylate, polyvinyl pyrrolidinone),fluorinated polymers such as polytetrafluoroethylene, and celluloseesters. Suitable matrices can be nondegrading or can degrade with time,releasing the compound or compounds. A compound provided herein can beapplied to the surface of the stent by various methods such as dip/spincoating, spray coating, dip-coating, and/or brush-coating. A compoundprovided herein can be applied in a solvent and the solvent can beallowed to evaporate, thus forming a layer of compound onto the stent.Alternatively, the compound can be located in the body of the stent orgraft, for example in microchannels or micropores. When implanted, thecompound diffuses out of the body of the stent to contact the arterialwall. Such stents can be prepared by dipping a stent manufactured tocontain such micropores or microchannels into a solution of a compoundprovided herein in a suitable solvent, followed by evaporation of thesolvent. Excess drug on the surface of the stent can be removed via anadditional brief solvent wash. In yet another embodiment, a compoundprovided herein can be covalently linked to a stent or graft. A covalentlinker can be used which degrades in vivo, leading to the release of acompound provided herein. Any bio-labile linkage can be used for such apurpose, such as ester, amide or anhydride linkages. A compound providedherein can additionally be administered intravascularly from a balloonused during angioplasty. Extravascular administration of a compoundprovided herein via the pericardia or via advential application offormulations provided herein can also be performed to decreaserestenosis.

A variety of stent devices which can be used as described are disclosed,for example, in the following references, all of which are herebyincorporated by reference: U.S. Pat. Nos. 5,451,233; 5,040,548;5,061,273; 5,496,346; 5,292,331; 5,674,278; 3,657,744; 4,739,762;5,195,984; 5,292,331; 5,674,278; 5,879,382; and 6,344,053.

Formulations for Controlled Release Administration:

In some embodiments, provided herein are pharmaceutical compositions forcontrolled release administration containing a polymorph provided hereinor a pharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, chelates, non-covalent complexes, isomers,prodrugs, and isotopically labeled derivatives) thereof, and apharmaceutical excipient suitable for controlled release administration.In some embodiments, provided herein are pharmaceutical compositions forcontrolled release administration containing: (i) an effective amount ofa disclosed polymorph or a pharmaceutically acceptable form (e.g.,pharmaceutically acceptable salts, hydrates, solvates, chelates,non-covalent complexes, isomers, prodrugs, and isotopically labeledderivatives) thereof; optionally (ii) an effective amount of one or moresecond agents; and (iii) one or more pharmaceutical excipients suitablefor controlled release administration. In some embodiments, thepharmaceutical composition further contains: (iv) an effective amount ofa third agent.

Active agents such as the compounds provided herein can be administeredby controlled release means or by delivery devices that are well knownto those of ordinary skill in the art. Examples include, but are notlimited to, those described in U.S. Pat. Nos. 3,845,770; 3,916,899;3,536,809; 3,598,123; and 4,008,719; 5,674,533; 5,059,595; 5,591,767;5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566;5,739,108; 5,891,474; 5,922,356; 5,972,891; 5,980,945; 5,993,855;6,045,830; 6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970;6,267,981; 6,376,461; 6,419,961; 6,589,548; 6,613,358; 6,699,500 each ofwhich is incorporated herein by reference. Such dosage forms can be usedto provide slow or controlled release of one or more active agentsusing, for example, hydropropylmethyl cellulose, other polymer matrices,gels, permeable membranes, osmotic systems, multilayer coatings,microparticles, liposomes, microspheres, or a combination thereof toprovide a given release profile in varying proportions. Suitablecontrolled release formulations known to those of ordinary skill in theart, including those described herein, can be readily selected for usewith the active agents provided herein. Thus, the pharmaceuticalcompositions provided encompass single unit dosage forms suitable fororal administration such as, but not limited to, tablets, capsules,gelcaps, and caplets that are adapted for controlled release.

All controlled release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non controlledcounterparts. In some embodiments, the use of a controlled releasepreparation in medical treatment is characterized by a minimum of drugsubstance being employed to cure or control the disease, disorder, orcondition in a minimum amount of time. Advantages of controlled releaseformulations include extended activity of the drug, reduced dosagefrequency, and increased subject compliance. In addition, controlledrelease formulations can be used to affect the time of onset of actionor other characteristics, such as blood levels of the drug, and can thusaffect the occurrence of side (e.g., adverse) effects.

In some embodiments, controlled release formulations are designed toinitially release an amount of a compound (e.g., a polymorph) asdisclosed herein or a pharmaceutically acceptable form (e.g.,pharmaceutically acceptable salts, hydrates, solvates, chelates,non-covalent complexes, isomers, prodrugs, and isotopically labeledderivatives) thereof, that promptly produces a therapeutic effect, andgradually and continually release other amounts of the compound tomaintain this level of therapeutic or prophylactic effect over anextended period of time. In order to maintain this constant level of theFormula (I) in the body, the compound should be released from the dosageform at a rate that will replace the amount of drug being metabolizedand excreted from the body. Controlled release of an active agent can bestimulated by various conditions including, but not limited to, pH,temperature, enzymes, water, or other physiological conditions orcompounds.

In certain embodiments, the pharmaceutical composition can beadministered using intravenous infusion, an implantable osmotic pump, atransdermal patch, liposomes, or other modes of administration. In oneembodiment, a pump can be used (see, Sefton, CRC Crit. Ref Biomed Eng.14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N.Engl. J. Med 321:574 (1989)). In another embodiment, polymeric materialscan be used. In yet another embodiment, a controlled release system canbe placed in a subject at an appropriate site determined by apractitioner of skill, i.e., thus requiring only a fraction of thesystemic dose (see, e.g., Goodson, Medical Applications of ControlledRelease, 115-138 (vol. 2, 1984). Other controlled release systems arediscussed in the review by Langer, Science 249:1527-1533 (1990). The oneor more active agents can be dispersed in a solid inner matrix, e.g.,polymethylmethacrylate, polybutylmethacrylate, plasticized orunplasticized polyvinylchloride, plasticized nylon, plasticizedpolyethyleneterephthalate, natural rubber, polyisopene, polyisobutylene,polybutadiene, polyethylene, ethylene-vinylacetate copolymers, siliconerubbers, polydimethylsiloxanes, silicone carbonate copolymers,hydrophilic polymers such as hydrogels of esters of acrylic andmethacrylic acid, collagen, cross-linked polyvinylalcohol andcross-linked partially hydrolyzed polyvinyl acetate, that is surroundedby an outer polymeric membrane, e.g., polyethylene, polypropylene,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers,ethylene/vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride,vinylchloride copolymers with vinyl acetate, vinylidene chloride,ethylene and propylene, ionomer polyethylene teraphthalate, butyl rubberepichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer, andethylene/vinyloxyethanol copolymer, that is insoluble in body fluids.The one or more active agents then diffuse through the outer polymericmembrane in a release rate controlling step. The percentage of activeagent in such parenteral compositions is highly dependent on thespecific nature thereof, as well as the needs of the subject.

Dosage:

A compound (e.g., a polymorph) described herein or a pharmaceuticallyacceptable form (e.g., pharmaceutically acceptable salts, hydrates,solvates, chelates, non-covalent complexes, isomers, prodrugs, andisotopically labeled derivatives) thereof can be delivered in the formof pharmaceutically acceptable compositions which comprise atherapeutically effective amount of one or more compounds or apharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, chelates, non-covalent complexes, isomers,prodrugs, and isotopically labeled derivatives) thereof described hereinand/or one or more additional therapeutic agents such as achemotherapeutic, formulated together with one or more pharmaceuticallyacceptable excipients. In some instances, the compound or apharmaceutically acceptable form described herein and the additionaltherapeutic agent are administered in separate pharmaceuticalcompositions and can (e.g., because of different physical and/orchemical characteristics) be administered by different routes (e.g., onetherapeutic is administered orally, while the other is administeredintravenously). In other instances, the compound described herein or apharmaceutically acceptable form and the additional therapeutic agentcan be administered separately, but via the same route (e.g., bothorally or both intravenously). In still other instances, the compounddescribed herein or a pharmaceutically acceptable form and theadditional therapeutic agent can be administered in the samepharmaceutical composition.

In one embodiment, polymorphs provided herein can be administered indosages. It is known in the art that due to possible intersubjectvariability in pharmacokinetics, individualization of dosing regimen canbe employed for optimal therapy. Dosing for a compound provided hereincan be found by routine experimentation in light of the instantdisclosure.

In one embodiment, the amount of a compound administered will bedependent on the mammal being treated, the severity of the disorder orcondition, the route of administration, the rate of administration, thedisposition of the compound, the rate of excretion or metabolism of theparticular compound being employed, the rate and extent of absorption,the duration of the treatment, other drugs, compounds and/or materialsused in combination with the particular compound employed, the age, sex,weight, condition, general health and prior medical history of thepatient being treated, the discretion of the prescribing physician, andlike factors well known in the medical arts. In one embodiment, aneffective dosage is in a range of about 0.001 to about 100 mg per kgbody weight per day, or about 1 to about 35 mg/kg/day, in single ordivided dose(s). In one embodiment, for a 70 kg human, an effectivedosage can amount to about 0.05 to 7 g/day, or about 0.05 to about 2.5g/day. In some instances, dosage levels below the lower limit of theaforesaid range can be more than adequate, while in other cases stilllarger doses can be employed without causing any harmful side effect,e.g., in some embodiments, by dividing such larger doses into severalsmall doses for administration throughout the day.

In general, a suitable daily dose of a compound described herein and/ora chemotherapeutic will be that amount of the compound which, in someembodiments, can be the lowest dose effective to produce a therapeuticeffect. Such an effective dose will generally depend upon the factorsdescribed above. Generally, doses of the compounds described herein fora patient, when used for the indicated effects, can range from about0.0001 mg to about 100 mg per day, or about 0.001 mg to about 100 mg perday, or about 0.01 mg to about 100 mg per day, or about 0.1 mg to about100 mg per day, or about 0.0001 mg to about 500 mg per day, or about0.001 mg to about 500 mg per day, or about 0.01 mg to 1000 mg, or about0.01 mg to about 500 mg per day, or about 0.1 mg to about 500 mg perday, or about 1 mg to 50 mg per day, or about 5 mg to 40 mg. Anexemplary dosage is about 10 to 30 mg per day. In some embodiments, fora 70 kg human, a suitable dose would be about 0.05 to about 7 g/day,such as about 0.05 to about 2.5 g/day. Actual dosage levels of theactive ingredients in the pharmaceutical compositions described hereincan be varied so as to obtain an amount of the active ingredient whichis effective to achieve a therapeutic response for a particular patient,composition, and mode of administration, without being toxic to thepatient. In some instances, dosage levels below the lower limit of theaforesaid range can be mom than adequate, while in other cases stilllarger doses can be employed without causing any harmful side effect,e.g., by dividing such larger doses into several small doses foradministration throughout the day.

In some embodiments, a compound provided herein is administered in asingle dose. In some embodiments, such administration is by injection,e.g., intravenous injection, in order to introduce the agent quickly. Inother embodiments, such administration is by oral administration, e.g.,for ease of administration and patient compliance. Other routes can alsobe used as appropriate. In some embodiments, a single dose of a compoundprovided herein can be used for treatment of an acute condition.

In some embodiments, a compound provided herein is administered inmultiple doses. In one embodiment, dosing can be about once, twice,three times, four times, five times, six times, or more than six timesper day. In one embodiment, dosing can be about once a month, once everytwo weeks, once a week, or once every other day. In another embodiment,a compound provided herein and another agent are administered togetherabout once per day to about 6 times per day. In another embodiment, theadministration of a compound provided herein and an agent continues forless than about 7 days. In yet another embodiment, the administrationcontinues for more than about 6, 10, 14, or 28 days, two months, sixmonths, or one year. In some embodiments, continuous dosing is achievedand maintained as long as necessary. In some embodiments, a compoundprovided herein is administered in cycles (e.g., a treatment periodfollowed by a treatment-free period, and repeat the cycle for as long asnecessary).

In some embodiments, the compounds can be administered daily, everyother day, three times a week, twice a week, weekly, or bi-weekly. Thedosing schedule can include a “drug holiday,” i.e., the drug can beadministered for two weeks on, one week off, or three weeks on, one weekoff, or four weeks on, one week off, etc., or continuously, without adrug holiday. The compounds can be administered orally, intravenously,intraperitoneally, topically, transdermally, intramuscularly,subcutaneously, intranasally, sublingually, or by any other route.

In one embodiment, administration of an agent provided herein cancontinue as long as necessary. In some embodiments, an agent providedherein is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28day(s). In some embodiments, an agent provided herein is administeredfor less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day(s). In someembodiments, an agent provided herein is administered chronically on anongoing basis, e.g., for the treatment of chronic disorders.

In one embodiment, an effective amount of a compound provided herein canbe administered in either single or multiple doses by any of theaccepted modes of administration of agents having similar utilities,including orally, parenterally, subcutaneously, intravenously,intraperitoneally, intramuscularly, intraarterially, topically,rectally, buccally, intranasally, transdermally, or as an inhalant. Inone embodiment, the compound is administered orally as a single doseonce a day. In other embodiments, the compound is administered orally atmultiple doses, e.g., at least two, three or more doses per day.

In certain embodiments, the compound is administered, e.g., orally, as asingle dose once a day of about 50 mg or less, about 40 mg or less,about 30 mg or less, about 25 mg or less, about 20 mg or less, about 15mg or less, about 12.5 mg or less, about 10 mg or less, about 5 mg orless, about 4 mg or less, about 3 mg or less, about 2 mg or less, orabout 1 mg or less (e.g., about 0.9 mg, about 0.8 mg, about 0.7 mg,about 0.6 mg, about 0.5 mg, about 0.4 mg, about 0.3 mg, about 0.2 mg,about 0.1 mg, or about 0.05 mg or less). In certain embodiments, thecompound is administered, e.g., orally, as a single dose once a dayranging from about 0.05 mg to about 50 mg, about 0.1 mg to about 45 mg,about 0.2 mg to about 40 mg, about 0.5 mg to about 35 mg, about 0.7 mgto about 30 mg, about 1 mg to about 30 mg, about 2 mg to about 25 mg,about 5 mg to about 20 mg, about 7 mg to about 15 mg, about 10 mg toabout 12 mg, about 5 mg to about 10 mg, about 1 mg to about 5 mg, about0.01 mg to about 1 mg, about 0.01 mg to about 0.05 mg, or about 0.05 mgto about 1 mg.

In certain embodiments, the compound is administered, e.g., orally, atmultiple doses per day (e.g., twice a day), wherein each dose is about50 mg or less, about 40 mg or less, about 30 mg or less, about 25 mg orless, about 20 mg or less, about 15 mg or less, about 12.5 mg or less,about 10 mg or less, about 5 mg or less, about 4 mg or less, about 3 mgor less, about 2 mg or less, or about 1 mg or less (e.g., about 0.9 mg,about 0.8 mg, about 0.7 mg, about 0.6 mg, about 0.5 mg, about 0.4 mg,about 0.3 mg, about 0.2 mg, about 0.1 mg, or about 0.05 mg or less). Incertain embodiments, the compound is administered, e.g., orally, atmultiple doses per day (e.g., twice a day), wherein each dose rangesfrom about 0.05 mg to about 50 mg, about 0.1 mg to about 45 mg, about0.2 mg to about 40 mg, about 0.5 mg to about 35 mg, about 0.7 mg toabout 30 mg, about 1 mg to about 30 mg, about 2 mg to about 25 mg, about5 mg to about 20 mg, about 7 mg to about 15 mg, about 10 mg to about 12mg, about 5 mg to about 10 mg, about 1 mg to about 5 mg, about 0.01 mgto about 1 mg, about 0.01 mg to about 0.05 mg, or about 0.05 mg to about1 mg.

Since the compounds described herein can be administered in combinationwith other treatments (such as additional chemotherapeutics, radiationor surgery), the doses of each agent or therapy can be lower than thecorresponding dose for single-agent therapy. The dose for single-agenttherapy can range from, for example, about 0.0001 to about 200 mg, orabout 0.001 to about 100 mg, or about 0.01 to about 100 mg, or about 0.1to about 100 mg, or about 0.05 mg to about 50 mg, or about 1 to about 50mg per day.

When a compound provided herein, is administered in a pharmaceuticalcomposition that comprises one or more agents, and the agent has ashorter half-life than the compound provided herein unit dose forms ofthe agent and the compound provided herein can be adjusted accordingly.

In one aspect, compositions are featured, which include the compound ofFormula (I) (e.g., a composition including one or more polymorphic formsof the compound of Formula (I), e.g., polymorph Form C), when dosed at adose range of 0.05 mg once a day (QD) to 50 mg twice a day (BID) ofactive compound, are capable of producing an amount of compoundsufficient to achieve a mean steady state area under the concentrationtime curve, AUC (e.g., AUC₀₋₂₄ or AUC_(tau) ss), of at least about 0.5ng*hr/mL, at least about 1 ng*hr/mL, at least about 2.5 ng*hr/mL, atleast about 5 ng*hr/mL, at least about 10 ng*hr/mL, at least about 25ng*hr/mL, at least about 50 ng*hr/mL, at least about 100 ng*hr/mL, atleast about 150 ng*hr/mL, at least about 200 ng*hr/mL, at least about250 ng*hr/mL, at least about 300 ng*hr/mL, at least about 500 ng*hr/mL,at least about 750 ng*hr/mL, at least about 850 ng*hr/mL, at least about950 ng*hr/mL, at least about 1,000 ng*hr/mL, at least about 1,500ng*hr/mL, at least about 2,000 ng*hr/mL, at least about 3,000 ng*hr/mL,at least about 5,000 ng*hr/mL, at least about 10,000 ng*hr/mL, at leastabout 12,000 ng*hr/mL, at least about 15,000 ng*hr/mL, at least about20,000 ng*hr/mL, at least about 25,000 ng*hr/mL, at least about 30,000ng*hr/mL, at least about 50,000 ng*hr/mL, at least about 75,000ng*hr/mL, at least about 100,000 ng*hr/mL, at least about 200,000ng*hr/mL, or at least about 300,000 ng*hr/mL. In certain embodiments,the AUC (e.g., AUC₀₋₂₄ or AUC_(tau) ss) of the composition when dosed ata dose range of about 0.05 mg QD to about 50 mg BID of active compound,is at least about 5 ng*hr/mL, at least about 50 ng*hr/mL, at least about100 ng*hr/mL, at least about 150 ng*hr/mL, at least about 200 ng*hr/mL,at least about 300 ng*hr/mL, at least about 400 ng*hr/mL, at least about500 ng*hr/mL, at least about 600 ng*hr/mL, at least about 700 ng*hr/mL,at least about 800 ng*hr/mL, at least about 900 ng*hr/mL, at least about1,000 ng*hr/mL, at least about 1,500 ng*hr/mL, at least about 2,000ng*hr/mL, at least about 2,500 ng*hr/mL, at least about 3,000 ng*hr/mL,at least about 5,000 ng*hr/mL, at least about 10,000 ng*hr/mL, at leastabout 15,000 ng*hr/mL, at least about 20,000 ng*hr/mL, at least about25,000 ng*hr/mL, or at least about 30,000 ng*hr/mL. In otherembodiments, the AUC (e.g., AUC₀₋₂₄ or AUC_(tau) ss) of the compositionwhen dosed at a dose range of about 0.05 mg QD to about 50 mg BID ofactive compound, is in the range of about 0.5 ng*hr/mL to about 300,000ng*hr/mL, about 1 ng*hr/mL to about 200,000 ng h/mL, about 2.5 ng*hr/mLto about 250,000 ng*hr/mL, about 5 ng*hr/mL to about 30,000 ng*hr/mL,about 10 ng*hr/mL to about 200,000 ng*hr/mL, about 25 ng*hr/mL to about100,000 ng*hr/mL, about 50 ng*hr/mL to about 75,000 ng*hr/mL, about 100ng*hr/mL to about 50,000 ng*hr/mL, about 200 ng*hr/mL to about 40,000ng*hr/mL, about 500 ng*hr/mL to about 30,000 ng*hr/mL, about 1,000ng*hr/mL to about 25,000 ng*hr/mL, about 700 ng*hr/mL to about 15,000ng*hr/mL, about 500 ng*hr/mL to about 10,000 ng*hr/mL, about 1,000ng*hr/mL to about 5,000 ng*hr/mL, about 10,000 ng*hr/mL to about 50,000ng*hr/mL, about 20,000 ng*hr/mL to about 40,000 ng*hr/mL, or about25,000 ng*hr/mL to about 30,000 ng*hr/mL. In one embodiment, the AUC(e.g., AUC₀₋₂₄ or AUC_(tau) ss) of the composition when dosed at a doserange of about 0.05 mg QD to about 50 mg BID of active compound, is inthe range of about 5 ng*hr/mL to about 30,000 ng*hr/mL, about 1000ng*hr/mL to about 15,000 ng*hr/mL, about 2500 ng*hr/mL to about 10,000ng*hr/mL, about 100 ng*hr/mL to about 3,500 ng*hr/mL, about 145 ng*hr/mLto about 3,000 ng*hr/mL, about 250 ng*hr/mL to about 2,500 ng*hr/mL,about 300 ng*hr/mL to about 2,500 ng*hr/mL, about 500 ng*hr/mL to about2,300 ng*hr/mL, about 800 ng*hr/mL to about 2,200 ng*hr/mL, about 140ng*hr/mL to about 900 ng*hr/mL, about 500 ng*hr/mL to about 10,000ng*hr/mL, about 1,000 ng*hr/mL to about 5,000 ng*hr/mL, about 10,000ng*hr/mL to about 50,000 ng*hr/mL, about 20,000 ng*hr/mL to about 40,000ng*hr/mL, or about 25,000 ng*hr/mL to about 30,000 ng*hr/mL.

In one embodiment, the compositions that include the compound of Formula(I), when dosed at a dose range of about 1 mg to about 30 mgadministered to a human as a single oral dose once a day (QD) of activecompound, are capable of producing an amount of compound sufficient toachieve an AUC, e.g., AUC₀₋₂₄, of at least about 40 ng*hr/mL, at leastabout 50 ng*hr/mL, at least about 75 ng*hr/mL, at least about 100ng*hr/mL, at least about 150 ng*hr/mL, at least about 200 ng*hr/mL, atleast about 300 ng*hr/mL, at least about 400 ng*hr/mL, at least about500 ng*hr/mL, at least about 600 ng*hr/mL, at least about 700 ng*hr/mL,at least about 800 ng*hr/mL, at least about 900 ng*hr/mL, at least about1,000 ng*hr/mL, at least about 1,500 ng*hr/mL, at least about 2,000ng*hr/mL, at least about 2,500 ng*hr/mL, at least about 3,000 ng*hr/mL,at least about 5,000 ng*hr/mL, at least about 10,000 ng*hr/mL, at leastabout 15,000 ng*hr/mL, at least about 20,000 ng*hr/mL, at least about30,000 ng*hr/mL, or at least about 50,000 ng*hr/mL. In one embodiment,the AUC, e.g., AUC₀₋₂₄, of the composition when dosed at a dose range ofabout 1 mg to about 30 mg as a single oral dose once a day (QD) ofactive compound, is in the range of about 5 ng*hr/mL to about 30,000ng*hr/mL, about 100 ng*hr/mL to about 3,500 ng*hr/mL, about 145 ng*hr/mLto about 3,300 ng*hr/mL, about 200 ng*hr/mL to about 2,500 ng*hr/ml,about 300 ng*hr/mL to about 2,100 ng*hr/mL, about 500 ng*hr/mL to about2,000 ng*hr/mL, about 500 ng*hr/mL to about 5,000 ng*hr/mL, about 1,000ng*hr/mL to about 10,000 ng*hr/mL, about 10,000 ng*hr/mL to about 50,000ng*hr/mL, about 20,000 ng*hr/mL to about 40,000 ng*hr/mL, or about25,000 ng*hr/mL to about 30,000 ng*hr/mL.

In another embodiment, the compositions that include the compound ofFormula (I), when dosed at a dose range of about 1 mg to about 10 mg(e.g., evaluated on day 14 following 1, 2, 5, and 10 mg of repeateddosing (e.g., dosing was QD Days 1 and 14, and twice a day (BID) dosingon Days 2-13)) of active compound, are capable of producing an amount ofcompound sufficient to achieve a mean steady state area under theconcentration time curve (AUC_(tau) ss) of at least about 100 ng*hr/mL,at least about 200 ng*hr/mL, at least about 500 ng*hr/mL, at least about700 ng*hr/mL, at least about 1,000 ng*hr/mL, at least about 1,200ng*hr/mL, at least about 1,500 ng*hr/mL, at least about 2,000 ng*hr/mL,at least about 2,500 ng*hr/mL, at least about 3,000 ng*hr/mL, at leastabout 5,000 ng*hr/mL, at least about 10,000 ng*hr/mL, at least about15,000 ng*hr/mL, at least about 20,000 ng*hr/mL, at least about 25,000ng*hr/mL, or at least about 30,000 ng*hr/mL. In one embodiment, the AUC,e.g., AUC_(tau) ss, of the composition when dosed at a dose range ofabout 1 mg to about 10 mg (e.g., evaluated on day 14 following 1, 2, 5,and 10 mg of repeated dosing (e.g., dosing was QD Days 1 and 14, andtwice a day (BID) dosing on Days 2-13)), of active compound, is in therange of about 5 ng*hr/mL to about 30,000 ng*hr/mL, about 100 ng*hr/mLto about 3,500 ng*hr/mL, about 150 ng*hr/mL to about 3,300 ng*hr/mL,about 200 ng*hr/mL to about 2,500 ng*hr/mL, about 300 ng*hr/mL to about2,500 ng*hr/mL, about 500 ng*hr/mL to about 5,000 ng*hr/mL, about 1,000ng*hr/mL to about 10,000 ng*hr/mL, about 10,000 ng*hr/mL to about 50,000ng*hr/mL, about 20,000 ng*hr/mL to about 40,000 ng*hr/mL, or about25,000 ng*hr/mL to about 30,000 ng*hr/mL. As used herein, an “AUC₀₋₂₄”refers to an area under the mean steady state plasma concentration-timecurve up to 24 hours post-dose. “AUC_(tau) ss” refers to an AUC₀₋₂₄ forQD dosing, and AUC₀₋₁₂ for BID dosing. AUC corresponds to the area underthe plasma concentration-time over an interval. The AUC values areprovided throughout in nanogram hour per milliliter, abbreviated hereinas ng hr/mL or ng*h/mL. AUC values can be determined using conventionalmethods known in the art, see, e.g., Goodman and Gilman's ThePharmacological Basis of Therapeutics, 10th ed.; Hardman, J. G.,Limbird, L. E., Eds.; McGraw-Hill: New York, 2001.

In another aspect, compositions are disclosed, which include thecompound of Formula (I) (e.g., a composition including one or morepolymorphic forms of the compound of Formula (I), e.g., polymorph FormC), when dosed at a dose range of 0.05 mg once a day (QD) to 50 mg twicea day (BID) of active compound, are capable of producing an observedmaximum plasma concentration (Cmax) of at least about 0.05 ng/mL, atleast about 0.1 ng/mL, at least about 0.5 ng/mL, at least about 1 ng/mL,at least about 10 ng/mL, at least about 50 ng/mL, at least about 100ng/mL, at least about 150 ng/mL, at least about 200 ng/mL, at leastabout 300 ng/mL, at least about 400 ng/mL, at least about 500 ng/ml, atleast about 900 ng/mL, at least about 1,000 ng/mL, at least about 2,000ng/mL, at least about 3,000 ng/mL, at least about 4,000 ng/mL, at leastabout 5,000 ng/mL, at least about 10,000 ng/ml, at least about 20,000ng/mL, at least about 30,000 ng/mL, or at least about 40,000 ng/mL. Inother embodiments, the Cmax of the composition when dosed at a doserange of about 0.05 mg QD to about 50 mg BID of active compound, is atleast about 20 ng/mL, at least about 40 ng/mL, at least about 50 ng/mL,at least about 80 ng/mL, at least about 100 ng/mL, at least about 200ng/mL, at least about 500 ng/mL, at least about 750 ng/mL, at leastabout 1,000 ng/mL, at least about 1,500 ng/mL, at least about 5,000ng/mL, at least about 10,000 ng/mL, at least about 15,000 ng/mL, atleast about 20,000 ng/mL, at least about 30,000 ng/mL, or at least about40,000 ng/mL. In other embodiments, the Cmax of the composition whendosed at a dose range of about 0.05 mg QD to about 50 mg BID of activecompound, is in the range of about 0.5 ng/mL to about 40,000 ng/mL,about 0.1 ng/mL to about 20,000 ng/mL, about 1 ng/mL to about 20,000ng/mL, about 0.5 ng/mL to about 4,000 ng/mL, about 0.5 ng/mL to about10,000 ng/mL, about 1 ng/mL to about 3,000 ng/mL, about 10 ng/mL toabout 2,000 ng/mL, about 40 ng/mL to about 1,500 ng/mL, about 150 ng/mLto about 1,000 ng/mL, about 200 ng/mL to about 500 ng/mL, about 300ng/mL to about 400 ng/mL, about 500 ng/mL to 1,000 ng/mL, about 1,000ng/mL to about 5,000 ng/mL, about 5,000 ng/mL to about 10,000 ng/mL,about 10,000 ng/mL to about 20,000 ng/mL, about 20,000 ng/mL to about30,000 ng/mL, or about 30.000 ng/mL to about 40,000 ng/mL. In oneembodiment, the Cmax of the composition when dosed at a dose range ofabout 0.05 mg QD to about 50 mg BID of active compound, is in the rangeof about 0.5 ng/mL to about 4,000 ng/mL, about 20 ng/mL to about 1,500ng/mL, about 40 ng/mL to about 1,100 ng/mL, about 50 ng/mL to about1,000 ng/mL, about 80 ng/mL to about 900 ng/mL, about 100 ng/mL to about500 ng/mL, about 200 ng/mL to about 450 ng/mL, about 500 ng/mL to about1,000 ng/mL, about 1,000 ng/mL to about 5,000 ng/mL, about 5,000 ng/mLto about 10,000 ng/mL, about 10,000 ng/mL to about 20,000 ng/mL, about20,000 ng/mL to about 30,000 ng/mL, or about 30,000 ng/mL to about40,000 ng/mL.

In one embodiment, the compositions that include the compound of Formula(I), when dosed at a dose range of about 1 mg to about 30 mgadministered to a human as a single oral dose once a day (QD) of activecompound, are capable of producing a Cmax of at least about 20 ng/mL, atleast about 40 ng/mL, at least about 50 ng/mL, at least about 80 ng/mL,at least about 100 ng/mL, at least about 200 ng/mL, at least about 500ng/mL, at least about 750 ng/mL, at least about 1,000 ng/mL, or at leastabout 1,500 ng/mL. In other embodiments, the Cmax of the compositionwhen dosed at a dose range of about 1 mg to about 30 mg administered toa human as a single oral dose once a day (QD) of active compound, arecapable of producing a Cmax in the range of about 20 ng/mL to about1,500 ng/mL, about 40 ng/mL to about 1,200 ng/mL, about 50 ng/mL toabout 1,000 ng/mL, about 80 ng/mL to about 1,000 ng/mL, about 100 ng/mLto about 500 ng/mL, about 200 ng/mL to about 450 ng/ml, about 500 ng/mlto about 1,000 ng/mL, about 1,000 ng/mL to about 5,000 ng/mL, about5,000 ng/mL to about 10,000 ng/mL, about 10,000 ng/mL to about 20,000ng/mL, about 20,000 ng/mL to about 30,000 ng/mL, or about 30,000 ng/mLto about 40,000 ng/mL.

In another embodiment, the compositions that include the compound ofFormula (I), when dosed at a dose range of about 1 mg to about 10 mg(e.g., evaluated on day 14 following 1, 2, 5, and 10 mg of repeateddosing (e.g., dosing was QD Days 1 and 14, and twice a day (BID) dosingon Days 2-13)) of active compound, are capable of producing an amount ofcompound sufficient to achieve a Cmax of at least about 40 ng/mL, atleast about 50 ng/mL, at least about 60 ng/mL, at least about 100 ng/mL,at least about 200 ng/mL, at least about 300 ng/mL, at least about 400ng/mL, at least about 500 ng/mL, at least about 590 ng/mL, at leastabout 750 ng/mL, at least about 1,000 ng/mL, at least about 1,500 ng/mL,at least about 5,000 ng/mL, at least about 10,000 ng/mL, at least about15,000 ng/mL, at least about 20,000 ng/mL, at least about 30,000 ng/mL,or at least about 40,000 ng/mL. In one embodiment, the compositions thatinclude the compound of Formula (I) (e.g., polymorph Form C), when dosedat a dose of 1 mg (BID), 2 mg (BID), 5 mg (BID), or 10 mg (QD) as arepeat dosing (e.g., evaluated on day 14 following 1, 2, 5, and 10 mg ofrepeated dosing (e.g., dosing was QD Days 1 and 14, and twice a day(BID) dosing on Days 2-13)) of active compound, are capable of producinga Cmax in the range of about 50 ng/mL to about 600 ng/mL, about 60 ng/mLto about 400 ng/mL, about 100 ng/mL to about 360 ng/mL, about 140 ng/mLto about 250 ng/mL, about 250 ng/mL to about 1,000 ng/mL, about 1,000ng/mL to about 5,000 ng/mL, about 5,000 ng/mL to about 10,000 ng/mL,about 10,000 ng/mL to about 20,000 ng/nL, about 20,000 ng/mL to about30,000 ng/mL, or about 30,000 ng/mL to about 40,000 ng/mL.

In one embodiment, the compositions that include the compound of Formula(I), when dosed at a dose range of 1 mg to 30 mg administered to a humanas a single oral dose once a day (QD) of active compound, have ahalf-life (t_(1/2)) of at least 3 hours, at least 5 hours, at least 6hours, at least 7 hours, at least 8 hours, or at least 10 hours. Inother embodiments, the compositions that include the compound of Formula(I), when dosed at a dose range of about 1 mg to about 30 mgadministered to a human as a single oral dose once a day (QD) of activecompound, have a half-life (t_(1/2)) in the range of about 3 hours to 10hours.

The Cmax and half-life (t_(1/2)) values can be determined usingconventional methods known in the art, see. e.g., Goodman and Gilman'sThe Pharmacological Basis of Therapeutics, 10th ed.; Hardman, J. G.,Limbird, L. E., Eds.; McGraw-Hill: New York, 2001. In one embodiment,the half-life (t_(1/2)) is calculated as 0.693/k_(el) (terminalelimination).

Kits:

In yet another embodiment, provided herein are kits. In one embodiment,the kits include a compound or polymorphs described herein or apharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, chelates, non-covalent complexes, isomers,prodrugs, and isotopically labeled derivatives) thereof, in suitablepackaging, and written material that can include instructions for use,discussion of clinical studies, listing of side effects, and the like.Such kits can also include information, such as scientific literaturereferences, package insert materials, clinical trial results, and/orsummaries of these and the like, which indicate or establish theactivities and/or advantages of the compound or composition, and/orwhich describe dosing, administration, side effects, drug interactions,and/or other information useful to the health care provider. Suchinformation can be based on the results of various studies, for example,studies using experimental animals involving in vivo models or studiesbased on human clinical trials.

In some embodiments, a memory aid is provided with the kit, e.g., in theform of numbers next to the tablets or capsules whereby the numberscorrespond with the days of the regimen which the tablets or capsules sospecified should be ingested. Another example of such a memory aid is acalendar printed on the card, e.g., as follows “First Week, Monday,Tuesday, . . . etc . . . . Second Week, Monday, Tuesday, . . . ” etc.Other variations of memory aids will be readily apparent. A “daily dose”can be a single tablet or capsule or several tablets or capsules to betaken on a given day.

Pharmaceutical packs and/or kits provided can comprise a providedcomposition and a container (e.g., a vial, ampoule, bottle, syringe,and/or dispenser package, or other suitable container). In someembodiments, provided kits can optionally further include a secondcontainer comprising a suitable aqueous carrier for dilution orsuspension of the provided composition for preparation of administrationto a subject. In some embodiments, contents of provided formulationcontainer and solvent container combine to form at least one unit dosageform.

In one embodiment, a single container can comprise one or morecompartments for containing a provided composition, and/or appropriateaqueous carrier for suspension or dilution. In some embodiments, asingle container can be appropriate for modification such that thecontainer can receive a physical modification so as to allow combinationof compartments and/or components of individual compartments. Forexample, a foil or plastic bag can comprise two or more compartmentsseparated by a perforated seal which can be broken so as to allowcombination of contents of two individual compartments once the signalto break the seal is generated. A pharmaceutical pack or kit can thuscomprise such multi-compartment containers including a providedcomposition and appropriate solvent and/or appropriate aqueous carrierfor suspension.

In some embodiments, the kits can further contain another agent. In someembodiments, the compound provided herein or a pharmaceuticallyacceptable form (e.g., pharmaceutically acceptable salts, hydrates,solvates, chelates, non-covalent complexes, isomers, prodrugs, andisotopically labeled derivatives) thereof and a second agent areprovided as separate compositions in separate containers within the kit.In some embodiments, the compound provided herein or a pharmaceuticallyacceptable form (e.g., pharmaceutically acceptable salts, hydrates,solvates, chelates, non-covalent complexes, isomers, prodrugs, andisotopically labeled derivatives) thereof and a second agent areprovided as a single composition within a container in the kit. Suitablepackaging and additional articles for use (e.g., measuring cup forliquid preparations, foil wrapping to minimize exposure to air, and thelike) are known in the art and can be included in the kit. Kitsdescribed herein can be provided, marketed and/or promoted to healthproviders, including physicians, nurses, pharmacists, formularyofficials, and the like. Kits can also, in some embodiments, be marketeddirectly to the consumer.

An example of such a kit is a so-called blister pack. Blister packs arewell known in the packaging industry and are being widely used for thepackaging of pharmaceutical unit dosage forms (tablets, capsules, andthe like). Blister packs generally consist of a sheet of relativelystiff material covered with a foil of a preferably transparent plasticmaterial. During the packaging process, recesses are formed in theplastic foil. The recesses have the size and shape of the tablets orcapsules to be packed. Next, the tablets or capsules are placed in therecesses and the sheet of relatively stiff material is scaled againstthe plastic foil at the face of the foil which is opposite from thedirection in which the recesses were formed. As a result, the tablets orcapsules are sealed in the recesses between the plastic foil and thesheet. The strength of the sheet is such that the tablets or capsulescan be removed from the blister pack by manually applying pressure onthe recesses whereby an opening is formed in the sheet at the place ofthe recess. The tablet or capsule can then be removed via said opening.

Kits can further comprise pharmaceutically acceptable vehicles that canbe used to administer one or more active agents. For example, if anactive agent is provided in a solid form that must be reconstituted forparenteral administration, the kit can comprise a sealed container of asuitable vehicle in which the active agent can be dissolved to form aparticulate-free sterile solution that is suitable for parenteraladministration. Examples of pharmaceutically acceptable vehiclesinclude, but are not limited to: Water for Injection USP; aqueousvehicles such as, but not limited to, Sodium Chloride Injection,Ringer's Injection, Dextrose Injection, Dextrose and Sodium ChlorideInjection, and Lactated Ringer's Injection; water-miscible vehicles suchas, but not limited to, ethyl alcohol, polyethylene glycol, andpolypropylene glycol; and non-aqueous vehicles such as, but not limitedto, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,isopropyl myristate, and benzyl benzoate.

The present disclosure further encompasses anhydrous pharmaceuticalcompositions and dosage forms comprising an active ingredient, sincewater can facilitate the degradation of some compounds. For example,water can be added (e.g., about 5%) in the pharmaceutical arts as ameans of simulating long-term storage in order to determinecharacteristics such as shelf-life or the stability of formulations overtime. Anhydrous pharmaceutical compositions and dosage forms can beprepared using anhydrous or low moisture containing ingredients and lowmoisture or low humidity conditions. For example, pharmaceuticalcompositions and dosage forms which contain lactose can be madeanhydrous if substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected. An anhydrouspharmaceutical composition can be prepared and stored such that itsanhydrous nature is maintained. Accordingly, anhydrous pharmaceuticalcompositions can be packaged using materials known to prevent exposureto water such that they can be included in suitable formulary kits.Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastic or the like, unit dose containers,blister packs, and strip packs.

In one embodiment, the polymorphs described herein or a pharmaceuticallyacceptable form (e.g., pharmaceutically acceptable salts, hydrates,solvates, chelates, non-covalent complexes, isomers, prodrugs, andisotopically labeled derivatives) thereof can be used in combinationwith the agents disclosed herein or other suitable agents, depending onthe condition being treated. Hence, in some embodiments, the polymorphsprovided herein or a pharmaceutically acceptable form (e.g.,pharmaceutically acceptable salts, hydrates, solvates, chelates,non-covalent complexes, isomers, prodrugs, and isotopically labeledderivatives) thereof can be co-administered with other agents asdescribed herein. When used in combination therapy, the polymorphsdescribed herein or a pharmaceutically acceptable form (e.g.,pharmaceutically acceptable salts, hydrates, solvates, chelates,non-covalent complexes, isomers, prodrugs, and isotopically labeledderivatives) thereof can be administered with a second agentsimultaneously or separately. This administration in combination caninclude simultaneous administration of the two agents in the same dosageform, simultaneous administration in separate dosage forms, and separateadministration. In some embodiments, a polymorph described herein andany of the second agents described herein can be formulated together inthe same dosage form and administered simultaneously. Alternatively, insome embodiments, a polymorph described herein or a pharmaceuticallyacceptable form (e.g., pharmaceutically acceptable salts, hydrates,solvates, chelates, non-covalent complexes, isomers, prodrugs, andisotopically labeled derivatives) thereof and any of the second agentsdescribed herein can be simultaneously administered, wherein both agentsare present in separate formulations. In another alternative, apolymorph described herein or a pharmaceutically acceptable form (e.g.,pharmaceutically acceptable salts, hydrates, solvates, chelates,non-covalent complexes, isomers, prodrugs, and isotopically labeledderivatives) thereof can be administered after, or before, theadministration of any of the second agents described herein. In aseparate administration protocol, a polymorph provided herein or apharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, chelates, non-covalent complexes, isomers,prodrugs, and isotopically labeled derivatives) thereof and any of thesecond agents described herein can be administered a few minutes apart,or a few hours apart, or a few days apart.

IV. Methods of Treatment

Phosphoinositide 3-kinases (PI3Ks) are members of a conserved family oflipid kinases that regulate numerous cell functions, includingproliferation, differentiation, cell survival and metabolism. Severalclasses of PI3Ks exist in mammalian cells, including Class IA subgroup(e.g., PI3K-α, β, δ), which are generally activated by receptor tyrosinekinases (RTKs); Class IB (e.g., PI3K-γ), which is activated by G-proteincoupled receptors, among others. PI3Ks exert their biological activitiesvia a “PI3K-mediated signaling pathway” that includes several componentsthat directly and/or indirectly transduce a signal triggered by a PI3K,including the generation of secondary messenger phophotidylinositol,3,4,5-triphosphate (PIP3) at the plasma membrane, activation ofheterotrimeric G protein signaling, and generation of further secondmessengers such as cAMP, DAG, and IP3, all of which leads to anextensive cascade of protein kinase activation (reviewed inVanhaesebroeck, B, el al. (2001) Annu Rev Biochem. 70.535-602). Forexample, PI3K-δ is activated by cellular receptors through interactionbetween the PI3K regulatory subunit (p85) SH2 domains, or through directinteraction with RAS. PIP3 produced by PI3K activates effector pathwaysdownstream through interaction with plextrin homology (PH) domaincontaining enzymes (e.g., PDK-1 and AKT [PKB]). (Fung-Leung W P. (2011)Cell Signal. 23(4):603-8). Unlike PI3K-δ, PI3K-γ is not a Class IA P3K,and is not associated with a regulatory subunit of the P85 family, butrather with a regulatory subunit in the p101 family. PI3K-γ isassociated with G-protein coupled receptors (GPCRs), and is responsiblefor the very rapid induction of PIP3, and can be also activated by RAS.

In some embodiments, provided herein are methods of modulating a PI3Kkinase activity (e.g., selectively modulating) by contacting the kinasewith an effective amount of a compound, or a pharmaceutically acceptableform (e.g., pharmaceutically acceptable salts, hydrates, solvates,chelates, non-covalent complexes, isomers, prodrugs, and isotopicallylabeled derivatives) thereof, or pharmaceutical compositions asdisclosed herein. Modulation can be inhibiting or activating kinaseactivity. In some embodiments, provided herein are methods of inhibitingkinase activity by contacting the kinase with an effective amount of acompound as disclosed herein in solution. In some embodiments, providedherein are methods of inhibiting the kinase activity by contacting acell, tissue, or organ that expresses the kinase of interest. In someembodiments, provided herein are methods of inhibiting kinase activityin a subject by administering into the subject an effective amount of acompound as disclosed herein.

In some embodiments, provided herein are methods of inhibiting kinaseactivity in a solution by contacting said solution with an amount of acompound provided herein sufficient to inhibit the activity of thekinase in said solution. In some embodiments, provided herein aremethods of inhibiting kinase activity in a cell by contacting said cellwith an amount of a compound provided herein sufficient to inhibit theactivity of the kinase in said cell. In some embodiments, providedherein are methods of inhibiting kinase activity in a tissue bycontacting said tissue with an amount of a compound provided hereinsufficient to inhibit the activity of the kinase in said tissue. In someembodiments, provided herein are methods of inhibiting kinase activityin an organism by contacting said organism with an amount of a compoundprovided herein sufficient to inhibit the activity of the kinase in saidorganism. In some embodiments, provided herein are methods of inhibitingkinase activity in an animal by contacting said animal with an amount ofa compound provided herein sufficient to inhibit the activity of thekinase in said animal. In some embodiments, provided herein are methodsof inhibiting kinase activity in a mammal by contacting said mammal withan amount of a compound provided herein sufficient to inhibit theactivity of the kinase in said mammal. In some embodiments, providedherein are methods of inhibiting kinase activity in a human bycontacting said human with an amount of a compound provided hereinsufficient to inhibit the activity of the kinase in said human.

In some embodiments, the % of kinase activity after contacting a kinasewith a compound provided herein is less than about 1, about 5, about 10,about 20, about 30, about 40, about 50, about 60, about 70, about 80,about 90, about 95, or about 99/6 of the kinase activity in the absenceof said contacting step. In some embodiments, the percentage ofinhibiting exceeds about 25%, about 30%, about 40%, about 50%, about60%, about 70%, about 80%, or about 90%. In some embodiments, providedherein are methods of inhibiting PI3 kinase activity in a subject(including mammals such as humans) by contacting said subject with anamount of a compound as disclosed herein sufficient to inhibit theactivity of the PI3 kinase in said subject.

In some embodiments, the kinase is a lipid kinase or a protein kinase.In some embodiments, the kinase is selected from a PI3 kinase includingdifferent isoforms such as PI3 kinase α, PI3 kinase β, PI3 kinase-γ, PI3kinase δ; DNA-PK; mTor, Abl. VEGFR, Ephrin receptor B4 (EphB4); TEKreceptor tyrosine kinase (TIE2); FMS-related tyrosine kinase 3 (FLT-3);Platelet derived growth factor receptor (PDGFR); RET; ATM. ATR; hSmg-1;Hek; Sc; Epidermal growth factor receptor (EGFR); KIT; Inulsin Receptor(IR) and IGFR.

In one embodiment, also provided herein are methods of modulating PI3kinase activity by contacting a PI3 kinase with an amount of a compoundprovided herein sufficient to modulate the activity of the PI3 kinase.Modulating can be inhibiting or activating PI3 kinase activity. In someembodiments, provided herein are methods of inhibiting PI3 kinaseactivity by contacting a PI3 kinase with an amount of a compoundprovided herein sufficient to inhibit the activity of the PI3 kinase. Insome embodiments, provided herein are methods of inhibiting PI3 kinaseactivity. In some embodiments, such inhibition can take place insolution, in a cell expressing one or more PI3 kinases, in a tissuecomprising a cell expressing one or more PI3 kinases, or in an organismexpressing one or more PI3 kinases. In some embodiments, provided hereinare methods of inhibiting PI3 kinase activity in an animal (includingmammal such as humans) by contacting said animal with an amount of acompound provided herein sufficient to inhibit the activity of the PI3kinase in said animal.

As used herein, a “PI3K-mediated disorder” refers to a disease orcondition involving aberrant PI3K-mediated signaling pathway. In oneembodiment, provided herein is a method of treating a PI3K mediateddisorder in a subject, the method comprising administering atherapeutically effective amount of a compound or a pharmaceuticalcomposition as disclosed herein. In some embodiments, provided herein isa method of treating a PI3K-δ or PI3K-γ mediated disorder in a subject,the method comprising administering a therapeutically effective amountof a compound or a pharmaceutical composition as disclosed herein. Insome embodiments, provided herein is a method for inhibiting at leastone of PI3K-δ or PI3K-γ, the method comprising contacting a cellexpressing PI3K in vitro or in vivo with an effective amount of thecompound or composition disclosed herein. P3Ks have been associated witha wide range of conditions, including immunity, cancer and thrombosis(reviewed in Vanhaesebroeck, B, el al. (2010) Current Topics inMicrobiology and Immunology, DOI 10.1007/82_2010_65). For example, Class1 P3Ks, particularly PI3K-γ and PI3K-δ isoforms, am highly expressed inleukocytes and have been associated with adaptive and innate immunity;thus, these PI3Ks are believed to be important mediators in inflammatorydisorders and hematologic malignancies (reviewed in Harris, S J at al.(2009) Curr Opin Investig Drugs 10(11):1151-62); Rommel C. et al. (2007)Nat Rev Immunol 7(3):191-201; Durand C A et al. (2009) J Immunol.183(9):5673-84; Dil N, Marshall A J. (2009) Mol Immunol. 46(10):1970-8;Al-Alwan M M et al. (2007) J Immunol. 178(4):2328-35; Zhang T T, et al.(2008) J Allergy Clin Immunol. 2008; 122(4):811-819.e2; Srinivasan L, etal. (2009) Cell 139(3):573-86).

Numerous publications support roles of PI3K-δ, PI3K-γ, and PI3K-β in thedifferentiation, maintenance, and activation of immune and malignantcells, as described in more detail below.

The importance of PI3K-δ in the development and function of B-cells issupported from inhibitor studies and genetic models. PI3K-δ is animportant mediator of B-cell receptor (BCR) signaling, and is upstreamof AKT, calcium flux, PLCγ, MAP kinase, P70S6k, and FOXO3a activation.PI3K-δ is also important in IL4R, S1P, and CXCR5 signaling, and has beenshown to modulate responses to toll-like receptors 4 and 9. Inhibitorsof PI3K-δ have shown the importance of PI3K-δ in B-cell development(Marginal zone and B1 cells), B-cell activation, chemotaxis, migrationand homing to lymphoid tissue, and in the control of immunoglobulinclass switching leading to the production of IgE. Clayton E et al.(2002) J Exp Med. 196(6):753-63; Bilancio A, et al. (2006) Blood107(2):642-50; Okkenhaug K. et al. (2002) Science 297(5583):1031-4;Al-Alwan M M et al. (2007) J Immunol. 178(4):2328-35; Zhang T T, et al.(2008) J Allergy Clin Immunol. 2008; 122(4):811-819.e2; Srinivasan L, etal. (2009) Cell 139(3):573-86)

In T-cells, PI3K-δ has been demonstrated to have a role in T-cellreceptor and cytokine signaling, and is upstream of AKT, PLCγ, andGSK3b. In PI3K-δ deletion or kinase-dead knock-in mice, or in inhibitorstudies, T-cell defects including proliferation, activation, anddifferentiation have been observed, leading to reduced T helper cell 2(TH2) response, memory T-cell specific defects (DTH reduction), defectsin antigen dependent cellular trafficking, and defects inchemotaxis/migration to chemokines (e.g., S1P, CCR7, CD62L). (Garçon F.et al. (2008) Blood 111(3):1464-71; Okkenhaug K et al. (2006). JImmunol. 177(8):5122-8; Soond D R, et al. (2010) Blood 115(11):2203-13;Reif K, (2004). J Immunol. 2004; 173(4):2236-40; Ji H. et al. (2007)Blood 110(8):2940-7; Webb L M, et al. (2005) J Immunol. 175(5):2783-7;Liu D, et al. (2010) J Immunol. 184(6):3098-105; Haylock-Jacobs S, etal. (2011) J Autoimmun. 2011; 36(3-4):278-87; Jarmin S J, et al. (2008)JClin Invest. 118(3):1154-64).

In neutrophils, PI3K-δ along with PI3K-γ, and PI3K-β, contribute to theresponses to immune complexes, FCgRII signaling, including migration andneutrophil respiratory burst. Human neutrophils undergo rapid inductionof PIP3 in response to formyl peptide receptor (FMLP) or complementcomponent C5a (C5a) in a PI3K-γ dependent manner, followed by a longerPIP3 production period that is PI3K-δ dependent, and is essential forrespiratory burst. The response to immune complexes is contributed byPI3K-δ, PI3K-γ, and PI3K-β, and is an important mediator of tissuedamage in models of autoimmune disease (Randis T M et al. (2008) Eur JImmunol. 38(5):1215-24; Pinho V, (2007) J Immunol. 179(11):7891-8; SadhuC. et al. (2003) J Immunol. 170(5):2647-54; Condliffe A M et al. (2005)Blood 106(4):1432-40).

In macrophages collected from patients with chronic obstructivepulmonary disease (COPD), glucocorticoid responsiveness can be restoredby treatment of the cells with inhibitors of PI3K-δ. Macrophages alsorely on PI3K-δ and PI3K-γ for responses to immune complexes through thearthus reaction (FCgR and C5a signaling) (Randis T M, et al. (2008) EurJ Immunol. 38(5):1215-24; Marwick J A et al. (2009) Am J Respir CritCare Med. 179(7):542-8; Konrad S, et al. (2008) J Biol Chem.283(48):33296-303).

In mast cells, stem cell factor-(SCF) and IL3-dependent proliferation,differentiation and function are PI3K-δ dependent, as is chemotaxis. Theallergen/IgE crosslinking of FCgR1 resulting in cytokine release anddegranulation of the mast cells is severely inhibited by treatment withPI3K-δ inhibitors, suggesting a role for PI3K-δ in allergic disease (AliK et al. (2004) Nature 431(7011):1007-11; Lee K S, et al. (2006) FASEBJ. 20(3):455-65; Kim M S, et a. (2008) Trends Immunol. 29(10):493-501).

Natural killer (NK) cells are dependent on both PI3K-δ and PI3K-γ forefficient migration towards chemokines including CXCL10, CCL3, SIP andCXCL12, or in response to LPS in the peritoneum (Guo H, et al. (2008) JExp Med. 205(10):2419-35; Tassi I, et al. (2007) Immunity 27(2):214-27;Saudemont A, (2009) Proc Natl Acad Sci USA. 106(14):5795-800; Kim N, etal. (2007) Blood 110(9):3202-8).

The roles of PI3K-δ, PI3K-γ, and PI3K-β in the differentiation,maintenance, and activation of immune cells support a role for theseenzymes in inflammatory disorders ranging from autoimmune diseases(e.g., rheumatoid arthritis, multiple sclerosis) to allergicinflammatory disorders, such as asthma and COPD. Extensive evidence isavailable in experimental animal models, or can be evaluated usingart-recognized animal models. In an embodiment, described herein is amethod of treating inflammatory disorders ranging from autoimmunediseases (e.g., rheumatoid arthritis, multiple sclerosis) to allergicinflammatory disorders, such as asthma and COPD using a compounddescribed herein.

For example, inhibitors of PI3K-δ and/or -γ have been shown to haveanti-inflammatory activity in several autoimmune animal models forrheumatoid arthritis (Williams, O. et al. (2010) Chem Biol,17(2):123-34; WO 2009/088986; WO2009/088880; WO 2011/008302). PI3K-δ isexpressed in the RA synovial tissue (especially in the synovial liningwhich contains fibroblast-like synoviocytes (FLS), and selective PI3K-δinhibitors have been shown to be effective in inhibiting synoviocytegrowth and survival (Bartok et al. (2010) Arthritis Rheum 62 Suppl10:362). Several PI3K-δ and w inhibitors have been shown to amelioratearthritic symptoms (e.g., swelling of joints, reduction of scrum-inducedcollagen levels, reduction of joint pathology and/or inflammation), inart-recognized models for RA, such as collagen-induced arthritis andadjuvant induced arthritis (WO 2009/088986; WO2009/088880; WO2011/008302).

The role of PI3K-δ has also been shown in models of T-cell dependentresponse, including the DTH model. In the murine experimental autoimmuneencephalomyelitis (EAE) model of multiple sclerosis, the PI3K-γ/δ-doublemutant mice are resistant. PI3K-δ inhibitors have also been shown toblock EAE disease induction and development of TH-17 cells both in vitroand in vivo (Haylock-Jacobs, S. et al. (2011) J. Autoimmunity36(3-4):278-87).

Systemic lupus erythematosus (SLE) is a complex disease that atdifferent stages requires memory T-cells, B-cell polyclonal expansionand differentiation into plasma cells, and the innate immune response toendogenous damage associated molecular pattern molecules (DAMPS), andthe inflammatory responses to immune complexes through the complementsystem as well as the Fc receptors. The role of PI3K-δ and PI3K-γtogether in these pathways and cell types suggest that blockade with aninhibitor would be effective in these diseases. A role for PI3K in lupusis also predicted by two genetic models of lupus. The deletion ofphosphatase and tensin homolog (PTEN) leads to a lupus-like phenotype,as does a transgenic activation of Class IA PI3Ks, which includesPI3K-δ. The deletion of PI3K-γ in the transgenically activated class IAlupus model is protective, and treatment with a PI3K-γ selectiveinhibitor in the murine MLR/Ipr model of lupus improves symptoms(Barber, D F et al. (2006)J. Immunol. 176(1): 589-93).

In allergic disease, PI3K-δ has been shown by genetic models and byinhibitor treatment to be essential for mast-cell activation in apassive cutaneous anaphalaxis assay (Ali K et al. (2008) J Immunol.180(4):2538-44; Ali K, (2004) Nature 431(7011):1007-11). In a pulmonarymeasure of response to immune complexes (Arthus reaction) a PI3K-δknockout is resistant, showing a defect in macrophage activation and C5aproduction. Knockout studies and studies with inhibitors for both PI3K-δand PI3K-γ support a role for both of these enzymes in the ovalbumininduced allergic airway inflammation and hyper-responsiveness model (LeeK S et al. (2006) FASEB J. 20(3):455-65). Reductions of infiltration ofeosinophils, neutrophils, and lymphocytes as well as TH2 cytokines (IL4,IL5, and IL13) were seen with both PI3K-δ specific and dual PI3K-δ andPI3K-γ inhibitors in the Ova induced asthma model (Lee K S et al. (2006)J Allergy Clin Immunol 118(2):403-9).

PI3K-δ and PI3K-γ inhibition can be used in treating COPD. In the smokedmouse model of COPD, the PI3K-δ knockout does not develop smoke inducedglucocorticoid resistance, while wild-type and PI3K-γ knockout mice do.An inhaled formulation of dual PI3K-δ and PI3K-γ inhibitor blockedinflammation in a LPS or smoke COPD models as measured by neutrophiliaand glucocorticoid resistance (Doukas J, et al. (2009) J Pharmacol ExpTher. 328(3):758-65).

Class 1 PI3Ks, particularly PI3K-δ and PI3K-γ isoforms, are alsoassociated with cancers (reviewed, e.g., in Vogt, P K et al. (2010) CurrTop Microbiol Immunol. 347:79-104; Fresno Vara, J A et al. (2004) CancerTreat Rev. 30(2):193-204; Zhao, L and Vogt, P K. (2008) Oncogene27(41):5486-96). Inhibitors of P3K, e.g., PI3K-δ and/or -γ, have beenshown to have anti-cancer activity (e.g., Courtney, K D et al. (2010) JClin Oncol. 28(6):1075-1083); Markman, B et al. (2010) Ann Oncol.21(4):683-91; Kong, D and Yamori, T (2009) Curr Med Chem.16(22):2839-54; Jimeno, A et al. (2009) J Clin Oncol. 27:156s (suppl;abstr 3542); Flinn, I W et al. (2009) J Clin Oncol. 27:156s (suppl;abstr 3543); Shapiro, G et al. (2009) J Clin Oncol. 27:146s (suppl;abstr 3500); Wagner, A J et al. (2009) J Clin Oncol. 27:146s (suppl;abstr 3501); Vogt, P K et al. (2006) Virology 344(1):131-8; Ward, S etal. (2003) Chem Biol. 10(3):207-13; WO 2011/041399; US 2010/0029693; US2010/0305096; US 2010/0305084). In an embodiment, described herein is amethod of treating cancer.

Types of cancer that can be treated with an inhibitor of PI3K(particularly, PI3K-δ and/or -γ) include, e.g., leukemia (e.g., chroniclymphocytic leukemia (CLL), acute myeloid leukemia (ALL), chronicmyeloid leukemia (CML) (e.g., Salmena, L et al. (2008) Cell 133:403-414;Chapuis, N et al. (2010) Clin Cancer Res. 16(22):5424-35; Khwaja, A(2010) Curr Top Macrobiol Immunol. 347:169-88); lymphoma (e.g.,non-Hodgkin's lymphoma or Hodgkin's lymphoma)(e.g., Salmena. L et al.(2008) Cell 133:403-414); lung cancer, e.g., non-small cell lung cancer,small cell lung cancer (e.g., Herrera, V A et al. (2011) Anticancer Res.31(3):849-54); melanoma (e.g., Haluska, F et al. (2007) Semin Oncol.34(6):546-54); prostate cancer (e.g., Sarker, D et al. (2009) ClinCancer Res. 15(15):4799-805); glioblastoma (e.g., Chen, J S et al.(2008) Mol Cancer Ther. 7:841-850); endometrial cancer (e.g., Bansal, Net al. (2009) Cancer Control. 16(1):8-13); pancreatic cancer (e.g.,Furukawa, T (2008) J Gastroenterol. 43(12):905-11); renal cell carcinoma(e.g., Porta, C and Figlin, R A (2009) J Urol. 182(6):2569-77);colorectal cancer (e.g., Saif, M W and Chu, E (2010) Cancer J.16(3):196-201); breast cancer (e.g., Torbett, N E et al. (2008) BiochemJ. 415:97-100); thyroid cancer (e.g., Brzczianska, E andPastuszak-Lcwandoska, D (2011) Front Biosci. 16:422-39); and ovariancancer (e.g., Mazzolctti, M and Broggini, M (2010) Curr Med Chem.17(36):443347).

Numerous publications support a role of PI3K-δ and PI3K-γ in treatinghematological cancers. PI3K-δ and PI3K-γ are highly expressed in theheme compartment, and some solid tumors, including prostate, breast andglioblastomas (Chen J. S. et al. (2008) Mol Cancer Ther. 7(4):841-50;Ikeda H. et al. (2010) Blood 116(9):1460-8).

In hematological cancers including acute myeloid leukemia (AML),multiple myeloma (MM), and chronic lymphocytic leukemia (CLL),overexpression and constitutive activation of PI3K-δ supports the modelthat PI3K-δ inhibition would be therapeutic Billottet C, et al. (2006)Oncogene 25(50):6648-59; Billottet C, et al. (2009) Cancer Res.69(3):1027-36; Meadows, S A, 52^(nd) Annual ASH Meeting and Exposition;2010 Dec. 4-7; Orlando, Fla.; Ikeda H, et al. (2010) Blood116(9):1460-8; Herman S E et al. (2010) Blood 116(12):2078-88; Herman SE et al. (2011). Blood 117(16):4323-7. In an embodiment, describedherein is a method of treating hematological cancers including, but notlimited to acute myeloid leukemia (AML), multiple myeloma (MM), andchronic lymphocytic leukemia (CLL).

A PI3K-δ inhibitor (CAL-101) has been evaluated in a phase 1 trial inpatients with haematological malignancies, and showed activity in CLL inpatients with poor prognostic characteristics. In CLL, inhibition ofPI3K-δ not only affects tumor cells directly, but it also affects theability of the tumor cells to interact with their microenvironment. Thismicroenvironment includes contact with and factors from stromal cells,T-cells, nurse like cells, as well as other tumor cells. CAL-101suppresses the expression of stromal and T-cell derived factorsincluding CCL3, CCL4, and CXCL13, as well as the CLL tumor cells'ability to respond to these factors. CAL-101 treatment in CLL patientsinduces rapid lymph node reduction and redistribution of lymphocytesinto the circulation, and affects tonic survival signals through theBCR, leading to reduced cell viability, and an increase in apoptosis.Single agent CAL-101 treatment was also active in mantle cell lymphomaand refractory non Hodgkin's lymphoma (Furman, R R, et al. 52^(nd)Annual ASH Meeting and Exposition; 2010 Dec. 4-7; Orlando, Fla.;Hoelleniegel, J, et al. 52^(nd) Annual ASH Meeting and Exposition; 2010Dec. 4-7; Orlando, Fla.; Webb, H K, et al. 52^(nd) Annual ASH Meetingand Exposition; 2010 Dec. 4-7; Orlando, Fla.; Meadows, et al. 52^(nd)Annual ASH Meeting and Exposition; 2010 Dec. 4-7; Orlando, Fla.; Kahl,B, et al. 52^(nd) Annual ASH Meeting and Exposition; 2010 Dec. 4-7;Orlando, Fla.; Lannutti B J, et al. (2011) Blood 117(2):591-4).

PI3K-δ inhibitors have shown activity against PI3K-δ positive gliomas invitro (Kashishian A, et al. Poster presented at: The AmericanAssociation of Cancer Research 102^(nd) Annual Meeting; 2011 Apr. 2-6;Orlando, Fla.). PI3K-β is the PI3K isoform that is most commonlyactivated in tumors where the PTEN tumor suppressor is mutated (Ward S,et al. (2003) Chem Biol. 10(3):207-13). In this subset of tumors,treatment with the PI3K-δ inhibitor either alone or in combination witha cytotoxic agent can be effective.

Another mechanism for PI3K-δ inhibitors to have an affect in solidtumors involves the tumor cells' interaction with theirmicro-environment. PI3K-δ, PI3K-γ, and PI3K-β are expressed in theimmune cells that infiltrate tumors, including tumor infiltratinglymphocytes, macrophages, and neutrophils. PI3K-δ inhibitors can modifythe function of these tumor-associated immune cells and how they respondto signals from the stroma, the tumor, and each other, and in this wayaffect tumor cells and metastasis (Hoellenriegel, J, et al. 52^(d)Annual ASH Meeting and Exposition; 2010 Dec. 4-7; Orlando, Fla.).

PI3K-δ is also expressed in endothelial cells. It has been shown thattumors in mice treated with PI3K-δ selective inhibitors are killed morereadily by radiation therapy. In this same study, capillary networkformation is impaired by the PI3K inhibitor, and it is postulated thatthis defect contributes to the greater killing with radiation. PI3K-δinhibitors can affect the way in which tumors interact with theirmicroenvironment, including stromal cells, immune cells, and endothelialcells and be therapeutic cither on its own or in conjunction withanother therapy (Meadows, S A, et al. Paper presented at: 52^(nd) AnnualASH Meeting and Exposition: 2010 Doc 4-7; Orlando, Fla.; Geng L, et al.(2004) Cancer Res. 64(14):4893-9).

In other embodiments, inhibition of PI3K (such as PI3K-δ and/or -γ) canbe used to treat a neuropsychiatric disorder, e.g., an autoimmune braindisorder. Infectious and immune factors have been implicated in thepathogenesis of several neuropsychiatric disorders, including, but notlimited to, Sydenham's chorea (SC) (Garvey, M. A. et al. (2005) J. ChildNeurol. 20:424-429), Tourette's syndrome (TS), obsessive compulsivedisorder (OCD) (Asbahr, F. R. et al. (1998) Am. J. Psychiatry155:1122-1124), attention deficit/hyperactivity disorder (AD/HD)(Hirschtritt, M. E, et al. (2008) Child Neuropsychol. 1:1-16; Peterson,B. S. et al. (2000) Arch. Gen. Psychiatry 57:364-372), anorexia nervosa(Sokol, M. S. (2000) J Child Adolesc. Psychopharmacol. 10:133-145;Sokol, M. S. et al. (2002) Am. J Psychiatry 159:1430-1432), depression(Leslie, D. L. et al. (2008) J Am. Acad. Child Adolesc. Psychiatry47:1166-1172), and autism spectrum disorders (ASD) (Hollander, E. et al.(1999) Am. J. Psychiatry 156:317-320; Margutti, P. et al. (2006) Curr.Neurovasc. Res. 3:149-157). A subset of childhood obsessive compulsivedisorders and tic disorders has been grouped as Pediatric AutoimmuneNeuropsychiatric Disorders Associated with Streptococci (PANDAS). PANDASdisorders provide an example of disorders where the onset andexacerbation of neuropsychiatric symptoms is preceded by a streptococcalinfection (Kurlan, R., Kaplan, E. L. (2004) Pediatrics 113:883-886;Garvey, M. A. et al. (1998) J. Clin. Neurol. 13:413-423). Many of thePANDAS disorders share a common mechanism of action resulting fromantibody responses against streptococcal associated epitopes, such asGlcNAc, which produces neurological effects (Kirvan. C. A. et al. (2006)J Neuroimmunol. 179:173-179). Autoantibodies recognizing central nervoussystem (CNS) epitopes are also found in scra of most PANDAS subjects(Yaddanapudi, K. et al. (2010) Mol. Psychiatry 15:712-726). Thus,several neuropsychiatric disorders have been associated with immune andautoimmune components, making them suitable for therapies that includePI3K-δ and/or -γ inhibition.

In certain embodiments, a method of treating (e.g., reducing orameliorating one or more symptoms of) a neuropsychiatric disorder,(e.g., an autoimmune brain disorder), using a PI3K-δ and/or -γ inhibitoris described, alone or in combination therapy. For example, one or morePI3K-δ and/or -γ inhibitors described herein can be used alone or incombination with any suitable therapeutic agent and/or modalities, e.g.,dietary supplement, for treatment of neuropsychiatric disorders.Exemplary neuropsychiatric disorders that can be treated with the PI3K-δand/or -γ inhibitors described herein include, but are not limited to,PANDAS disorders, Sydenham's chorma, Tourette's syndrome, obsessivecompulsive disorder, attention deficit/hyperactivity disorder, anorexianervosa, depression, and autism spectrum disorders. PervasiveDevelopmental Disorder (PDD) is an exemplary class of autism spectrumdisorders that includes Autistic Disorder, Asperger's Disorder,Childhood Disintegrative Disorder (CDD), Rett's Disorder and PDD-NotOtherwise Specified (PDD-NOS). Animal models for evaluating the activityof the PI3K-δ and/or -γ inhibitor are known in the art. For example, amouse model of PANDAS disorders is described in, e.g., Yaddanapudi, K.et al. (2010) supra; and Hoffman, K. I. et al. (2004) J. Neurosci.24:1780-1791.

Provided herein are methods of using compounds or pharmaceuticalcompositions provided herein to treat disease conditions, including butnot limited to, diseases associated with malfunctioning of one or moretype(s) of P3 kinase. For example, a detailed description of conditionsand disorders mediated by p110δ kinase activity is set forth in Sadu etal., WO 01/81346, which is incorporated herein by reference in itsentirety for all purposes.

In one embodiment, the treatment methods provided herein compriseadministering to a subject a therapeutically effective amount of acompound provided herein. In one embodiment, provided herein is a methodof treating an inflammation disorder, including autoimmune diseases in amammal. In one embodiment, the method comprises administering to saidmammal a therapeutically effective amount of a compound provided herein,or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrateor derivative thereof. Examples of autoimmune diseases include, but arenot limited to, acute disseminated encephalomyelitis (ADEM), Addison'sdisease, antiphospholipid antibody syndrome (APS), aplastic anemia,autoimmune hepatitis, coeliac disease, Crohn's disease, Diabetesmellitus (type 1), Goodpasture's syndrome, Graves' disease,Guillain-Barré syndrome (GBS), Hashimoto's disease, lupus erythematosus,multiple sclerosis, myasthenia gravis, opsoclonus myoclonus syndrome(OMS), optic neuritis, Ord's thyroiditis, oemphigus, polyarthritis,primary biliary cirrhosis, psoriasis, skin blistering bullouspemphigoid, rheumatoid arthritis, Reiter's syndrome, Takayasu'sarteritis, temporal arteritis (also known as “giant cell arteritis”),warm autoimmune hemolytic anemia, Wegener's granulomatosis, alopeciauniversalis, Chagas' disease, chronic fatigue syndrome, dysautonomia,endometriosis, hidradenitis suppurativa, interstitial cystitis,neuromyotonia, sarcoidosis, scleroderma, ulcerative colitis, vitiligo,and vulvodynia. In other embodiments, the disorders or diseaseconditions include bone-resorption disorders and thrombosis.

Inflammation takes on many forms and includes, but is not limited to,acute, adhesive, atrophic, catarrhal, chronic, cirrhotic, diffuse,disseminated, exudative, fibrinous, fibrosing, focal, granulomatous,hyperplastic, hypertrophic, interstitial, metastatic, necrotic,obliterative, parenchymatous, plastic, productive, proliferous,pseudomembranous, purulent, sclerosing, seroplastic, serous, simple,specific, subacute, suppurative, toxic, traumatic, and/or ulcerativeinflammation.

Exemplary inflammatory conditions include, but are not limited to,inflammation associated with acne, anemia (e.g., aplastic anemia,haemolytic autoimmune anaemia), asthma, arteritis (e.g., polyarteritis,temporal arteritis, periarteritis nodosa, Takayasu's arteritis),arthritis (e.g., crystalline arthritis, osteoarthrtis, psoriaticarthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis andReiter's arthritis), ankylosing spondylitis, amylosis, amyotrophiclateral sclerosis, autoimmune diseases, allergies or allergic reactions,atherosclerosis, bronchitis, bursitis, chronic prostatitis,conjunctivitis, Chagas disease, chronic obstructive pulmonary disease,cermatomyositis, diverticulitis, diabetes (e.g., type 1 diabetesmellitus, type 2 diabetes mellitus), a skin condition (e.g., psoriasis,eczema, burns, dermatitis, pruritus (itch)), endometriosis,Guillain-Barre syndrome, infection, ischaemic heart disease, Kawasakidisease, glomerulonephritis, gingivitis, hypersensitivity, headaches(e.g., migraine headaches, tension headaches), ileus (e.g.,postoperative ileus and ileus during sepsis), idiopathicthrombocytopenic purpura, interstitial cystitis (painful bladdersyndrome), gastrointestinal disorder (e.g., selected from peptic ulcers,regional enteritis, diverticulitis, gastrointestinal bleeding,eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis,eosinophilic gastritis, eosinophilic gastroenteritis, eosinophiliccolitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD, orits synonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn'sdisease, ulcerative colitis, collagenous colitis, lymphocytic colitis,ischaemic colitis, diversion colitis, Behcet's syndrome, indeterminatecolitis) and inflammatory bowel syndrome (IBS)), lupus, multiplesclerosis, morphea, myeasthenia gravis, myocardial ischemia, nephroticsyndrome, pemphigus vulgaris, pernicious ancaemia, peptic ulcers,polymyositis, primary biliary cirrhosis, neuroinflammation associatedwith brain disorders (e.g., Parkinson's disease, Huntington's disease,and Alzheimers disease), prostatitis, chronic inflammation associatedwith cranial radiation injury, pelvic inflammatory disease, reperfusioninjury, regional enteritis, rheumatic fever, systemic lupuserythematosus, cutaneous lupus erythematosus, schleroderma, scierodoma,sarcoidosis, spondyloarthopathies, Sjogren's syndrome, thyroiditis,transplantation rejection, tendonitis, trauma or injury (e.g.,frostbite, chemical irritants, toxins, scarring, burns, physicalinjury), vasculitis, vitiligo and Wegene's granulomatosis. In certainembodiments, the inflammatory disorder is selected from arthritis (e.g.,rheumatoid arthritis), inflammatory bowel disease, inflammatory bowelsyndrome, asthma, psoriasis, endometriosis, interstitial cystitis andprostatistis. In certain embodiments, the inflammatory condition is anacute inflammatory condition (e.g., for example, inflammation resultingfrom infection). In certain embodiments, the inflammatory condition is achronic inflammatory condition (e.g., conditions resulting from asthma,arthritis and inflammatory bowel disease). The compounds can also beuseful in treating inflammation associated with trauma andnon-inflammatory myalgia.

Immune disorders, such as auto-immune disorders, include, but are notlimited to, arthritis (including rheumatoid arthritis,spondyloarthopathies, gouty arthritis, degenerative joint diseases suchas osteoarthritis, systemic lupus erythematosus, Sjogren's syndrome,ankylosing spondylitis, undifferentiated spondylitis, Behcet's disease,haemolytic autoimmune anaemias, multiple sclerosis, amyotrophic lateralsclerosis, amylosis, acute painful shoulder, psoriatic, and juvenilearthritis), asthma, atherosclerosis, osteoporosis, bronchitis,tendonitis, bursitis, skin condition (e.g., psoriasis, eczema, burns,dermatitis, pruritus (itch)), enuresis, eosinophilic disease,gastrointestinal disorder (e.g., selected from peptic ulcers, regionalenteritis, diverticulitis, gastrointestinal bleeding, eosinophilicgastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilicgastritis, eosinophilic gastroenteritis, eosinophilic colitis),gastritis, diarrhea, gastroesophageal reflux disease (GORD, or itssynonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn's disease,ulcerative colitis, collagenous colitis, lymphocytic colitis, ischaemiccolitis, diversion colitis, Behcet's syndrome, indeterminate colitis)and inflammatory bowel syndrome (IBS)), and disorders ameliorated by agastroprokinetic agent (e.g., ileus, postoperative ileus and ileusduring sepsis; gastroesophageal reflux disease (GORD, or its synonymGERD); eosinophilic esophagitis, gastroparesis such as diabeticgastroparesis; food intolerances and food allergies and other functionalbowel disorders, such as non-ulcerative dyspepsia (NUD) and non-cardiacchest pain (NCCP, including costo-chondritis)).

In some embodiments, the method of treating inflammatory or autoimmunediseases comprises administering to a subject (e.g., a mammal) atherapeutically effective amount of a compound provided herein thatselectively inhibit PI3K-δ and/or PI3K-γ as compared to all other typesof PI3 kinases. Such selective inhibition of PI3K-δ and/or PI3K-γ can beadvantageous for treating any of the diseases or conditions describedherein. For example, without being limited by a particular theory,selective inhibition of PI3K-δ can inhibit inflammatory responsesassociated with inflammatory diseases, autoimmune disease, or diseasesrelated to an undesirable immune response, including but not limited to,asthma, emphysema, allergy, dermatitis, rheumatoid arthritis, psoriasis,lupus erythematosus, or graft versus host disease. Without being limitedby a particular theory, selective inhibition of PI3K-δ can furtherprovide for a reduction in the inflammatory or undesirable immuneresponse without a concomitant reduction in the ability to reduce abacterial, viral, and/or fungal infection. Without being limited by aparticular theory, selective inhibition of both PI3K-δ and PI3K-γ can beadvantageous for inhibiting the inflammatory response in the subject toa greater degree than that would be provided for by inhibitors thatselectively inhibit PI3K-δ or PI3K-γ alone. In one embodiment, one ormore of the methods provided herein are effective in reducing antigenspecific antibody production in vivo by about 2-fold, 3-fold, 4-fold,5-fold, 7.5-fold, 10-fold, 25-fold, 50-fold, 100-fold, 250-fold,500-fold, 750-fold, or about 1000-fold, or more. In another embodiment,one or mom of the methods provided herein are effective in reducingantigen specific IgG3 and/or IgGM production n vivo by about 2-fold,about 3-fold, about 4-fold, about 5-fold, about 7.5-fold, about 10-fold,about 25-fold, about 50-fold, about 100-fold, about 250-fold, about500-fold, about 750-fold, or about 1000-fold, or more.

In one embodiment, one of more of the methods provided herein areeffective in ameliorating symptoms associated with rheumatoid arthritis,including but not limited to, a reduction in the swelling of joints, areduction in serum anti-collagen levels, and/or a reduction in jointpathology, such as bone resorption, cartilage damage, pannus, and/orinflammation. In another embodiment, the methods provided herein areeffective in reducing ankle inflammation by at least about 2%, about 5%,about 10/6, about 15%, about 20%, about 25%, about 30%, about 50%, orabout 60%, or about 75% to about 90%. In another embodiment, the methodsprovided herein are effective in reducing knee inflammation by at leastabout 2%, about 5%, about 10%, about 15%, about 20%, about 25%, about30%, about 50%, or about 60%, or about 75% to about 90% or more. Instill another embodiment, the methods provided herein are effective inreducing serum anti-type II collagen levels by at least about 10%, about12%, about 15%, about 20%, about 24%, about 25%, about 30%, about 35%,about 50%, about 60%, about 75%, about 80%, about 86%, about 87%, orabout 90%, or more. In another embodiment, the methods provided hereinare effective in reducing ankle histopathology scores by about 5%, about10%, about 15%, about 20%, about 25%, about 30%, about 40%, about 50%,about 60%, about 75%, about 80%, or about 90%, or more. In still anotherembodiment, the methods provided herein are effective in reducing kneehistopathology scores by about 5%, about 10%, about 15%, about 20%,about 25%, about 30%, about 40%, about 50%, about 60%, about 75%, about80%, or about 90%, or more.

In other embodiments, provided herein are methods of using compounds orpharmaceutical compositions provided herein to treat respiratorydiseases, including but not limited to, diseases affecting the lobes oflung, pleural cavity, bronchial tubes, trachea, upper respiratory tract,or the nerves and muscle for breathing. For example, methods areprovided to treat obstructive pulmonary disease, including COPD. Chronicobstructive pulmonary disease (COPD) is an umbrella term for a group ofrespiratory tract diseases that are characterized by airflow obstructionor limitation. Conditions included in this umbrella term are: chronicbronchitis, emphysema, and bronchiectasis.

In another embodiment, the compounds described herein are used for thetreatment of asthma. Also, the compounds or pharmaceutical compositionsdescribed herein can be used for the treatment of endotoxemia andsepsis. In one embodiment, the compounds or pharmaceutical compositionsdescribed herein are used to for the treatment of rheumatoid arthritis(RA). In yet another embodiment, the compounds or pharmaceuticalcompositions described herein are used for the treatment of contact oratopic dermatitis. Contact dermatitis includes irritant dermatitis,phototoxic dermatitis, allergic dermatitis, photoallergic dermatitis,contact urticaria, systemic contact-type dermatitis, and the like.Irritant dermatitis can occur when too much of a substance is used onthe skin or when the skin is sensitive to certain substance. Atopicdermatitis, sometimes called eczema, is a kind of dermatitis, an atopicskin disease.

Also provided herein is a method of treating a hyperproliferativedisorder in a mammal comprising administering to said mammal atherapeutically effective amount of a compound provided herein, or apharmaceutically acceptable salt, ester, prodrug, solvate, hydrate orderivative thereof. In some embodiments, the hyperproliferative disorderis a mycloid, a myelodysplastic syndrome (MDS), a myeloproliferativedisease (MPD) or a mast cell disorder. In some embodiments, said methodrelates to the treatment of cancer such as acute myeloid leukemia,retinoblastoma, intraocular melanoma, or cancers of thymus, brain, lung,squamous cell, skin, eye, oral cavity and oropharyngeal, bladder,gastric, stomach, pancreatic, bladder, breast, cervical, head, neck,renal, kidney, liver, ovarian, prostate, colorectal, esophageal,testicular, gynecological, thyroid, CNS, or PNS, or AIDS-related (e.g.,Lymphoma and Kaposi's Sarcoma) or viral-induced cancer. In someembodiments, said method relates to the treatment of a non-canceroushyperproliferative disorder, such as benign hyperplasia of the skin(e.g., psoriasis), restenosis, or prostate (e.g., benign prostatichypertrophy (BPH)).

Also provided herein is a method of treating diseases related tovasculogenesis or angiogenesis in a mammal comprising administering tosaid mammal a therapeutically effective amount of a compound providedherein, or a pharmaceutically acceptable salt, ester, prodrug, solvate,hydrate or derivative thereof. In some embodiments, said method is fortreating a disease selected from the group consisting of tumorangiogenesis, chronic inflammatory disease such as rheumatoid arthritis,atherosclerosis, inflammatory bowel disease, skin diseases such aspsoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy,retinopathy of prematurity, age-related macular degeneration,hemangioma, glioma, melanoma, Kaposi's sarcoma, and ovarian, breast,lung, pancreatic, prostate, colon, and epidermoid cancer.

In one embodiment, patients that can be treated with compounds providedherein, or pharmaceutically acceptable salt, ester, prodrug, solvate,hydrate or derivative of said compounds, according to the methodsprovided herein include, for example, patients that have been diagnosedas having psoriasis; restenosis; atherosclerosis; BPH; breast cancersuch as a ductal carcinoma in duct tissue in a mammary gland, medullarycarcinomas, colloid carcinomas, tubular carcinomas, and inflammatorybreast cancer, ovarian cancer, including epithelial ovarian tumors, suchas adenocarcinoma in the ovary and an adenocarcinoma that has migratedfrom the ovary into the abdominal cavity; uterine cancer, cervicalcancer, such as adenocarcinoma in the cervix epithelial includingsquamous cell carcinoma and adenocarcinomas; prostate cancer, such as aprostate cancer selected from the following: an adenocarcinoma or anadenocarinoma that has migrated to the bone; pancreatic cancer, such asepitheliod carcinoma in the pancreatic duct tissue and an adenocarcinomain a pancreatic duct; bladder cancer, such as a transitional cellcarcinoma in urinary bladder, urothelial carcinomas (transitional cellcarcinomas), tumors in the urothelial cells that line the bladder,squamous cell carcinomas, adenocarcinomas, and small cell cancers;leukemia such as acute mycloid leukemia (AML), acute lymphocyticleukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairycell leukemia, myelodysplasia, myeloproliferative disorders, acutemyelogenous leukemia (AML), chronic myelogenous leukemia (CML),mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM),and myelodysplastic syndrome (MDS); bone cancer, lung cancer such asnon-small cell lung cancer (NSCLC), which is divided into squamous cellcarcinomas, adenocarcinomas, and large cell undifferentiated carcinomas,and small cell lung cancer, skin cancer such as basal cell carcinoma,melanoma, squamous cell carcinoma and actinic keratosis, which is a skincondition that sometimes develops into squamous cell carcinoma; eyeretinoblastoma; cutaneous or intraocular (eye) melanoma; primary livercancer (cancer that begins in the liver); kidney cancer; thyroid cancersuch as papillary, follicular, medullary and anaplastic; AIDS-relatedlymphoma such as diffuse large B-cell lymphoma, B-cell immunoblasticlymphoma and small non-cleaved cell lymphoma; Kaposi's Sarcoma;viral-induced cancers including hepatitis B virus (HBV), hepatitis Cvirus (HCV), and hepatocellular carcinoma; human lymphotropic virus-type1 (HTLV-1) and adult T-cell leukemia/lymphoma; and human papilloma virus(HPV) and cervical cancer, central nervous system cancers (CNS) such asprimary brain tumor, which includes gliomas (astrocytoma, anaplasticastrocytoma, or glioblastoma multiforme), Oligodendroglioma, Ependymoma,Meningioma, Lymphoma, Schwannoma, and Medulloblastoma; peripheralnervous system (PNS) cancers such as acoustic neuromas and malignantperipheral nerve sheath tumor (MPNST) including neurofibromas andschwannomas, malignant fibrous cytoma, malignant fibrous histiocytoma,malignant meningioma, malignant mesothelioma, and malignant mixedMüllerian tumor, oral cavity and oropharyngeal cancer such as,hypopharyngeal cancer, laryngeal cancer, nasopharyngeal cancer, andoropharyngeal cancer, stomach cancer such as lymphomas, gastric stromaltumors, and carcinoid tumors; testicular cancer such as germ cell tumors(GCTs), which include seminomas and nonseminomas, and gonadal stromaltumors, which include Leydig cell tumors and Sertoli cell tumors; thymuscancer such as to thymomas, thymic carcinomas, Hodgkin disease,non-Hodgkin lymphomas carcinoids or carcinoid tumors; rectal cancer;and/or colon cancer.

In one embodiment, patients that can be treated with compounds providedherein, or pharmaceutically acceptable salt, ester, prodrug, solvate,hydrate or derivative of said compounds, according to the methodsprovided herein include, for example, patients that have been diagnosedas having conditions including, but not limited to, acoustic neuroma,adenocarcinoma, adrenal gland cancer, anal cancer, angiosarcoma (e.g.,lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma), benignmonoclonal gammopathy, biliary cancer (e.g., cholangiocarcinoma),bladder cancer, breast cancer (e.g., adenocarcinoma of the breast,papillary carcinoma of the breast, mammary cancer, medullary carcinomaof the breast), brain cancer (e.g., meningioma; glioma, e.g.,astrocytoma, oligodendroglioma; medulloblastoma), bronchus cancer,cervical cancer (e.g., cervical adenocarcinoma), choriocarcinoma,chordoma, craniopharyngioma, colorectal cancer (e.g., colon cancer,rectal cancer, colorectal adenocarcinoma), epithelial carcinoma,ependymoma, endotheliosarcoma (e.g., Kaposi's sarcoma, multipleidiopathic hemorrhagic sarcoma), endometrial cancer, esophageal cancer(e.g., adenocarcinoma of the esophagus, Barrett's adenocarinoma), Ewingsarcoma, familiar hypereosinophilia, gastric cancer (e.g., stomachadenocarcinoma), gastrointestinal stromal tumor (GIST), head and neckcancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g.,oral squamous cell carcinoma (OSCC)), heavy chain disease (e.g., alphachain disease, gamma chain disease, mu chain disease), hemangioblastoma,inflammatory myofibroblastic tumors, immunocytic amyloidosis, kidneycancer (e.g., nephroblastoma a.k.a. Wilms' tumor, renal cell carcinoma),liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma),lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer(SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung),leukemia (e.g., acute lymphocytic leukemia (ALL), which includesB-lineage ALL and T-lineage ALL, chronic lymphocytic leukemia (CLL),prolymphocytic leukemia (PLL), hairy cell leukemia (HLL) andWaldenström's macroglobulinemia (WM); peripheral T cell lymphomas(PTCL), adult T cell leukemia/lymphoma (ATL), cutaneous T-cell lymphoma(CTCL), large granular lymphocytic leukemia (LGF), Hodgkin's disease andReed-Stemberg disease; acute myelocytic leukemia (AML), chronicmyelocytic leukemia (CML), chronic lymphocytic leukemia (CLL)), lymphoma(e.g., Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), follicularlymphoma, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma(MCL)), leiomyosarcoma (LMS), mastocytosis (e.g., systemicmastocytosis), multiple myeloma (MM), myelodysplastic syndrome (MDS),mesothelioma, myeloproliferative disorder (MPD) (e.g., polycythemia Vera(PV), essential thrombocytosis (ET), chronic myelomonocytic leukemia(CMML), agnogenic mycloid metaplasia (AMM) a.k.a. myelofibrosis (MF),chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML),chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)),neuroblastoma, neurofibroma (e.g., neurofibromatosis (NF) type 1 or type2, schwannomatosis), neuroendocrine cancer (e.g., gastroenteropanematicneuroendoctrine tumor (GEP-NET), carcinoid tumor), osteosarcoma, ovariancancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarianadenocarcinoma), Paget's disease of the vulva, Paget's disease of thepenis, papillary adenocarcinoma, pancreatic cancer (e.g., pancreaticandenocarcinoma, intraductal papillary mucinous neoplasm (IPMN)),pinealoma, primitive neuroectodermal tumor (PNT), prostate cancer (e.g.,prostate adenocarcinoma), rhabdomyosarcoma, retinoblastoma, salivarygland cancer, skin cancer (e.g., squamous cell carcinoma (SCC),keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)), small bowelcancer (e.g., appendix cancer), soft tissue sarcoma (e.g., malignantfibrous histiocytoma (MFH), liposarcoma, malignant peripheral nervesheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma),sebaceous gland carcinoma, sweat gland carcinoma, synovioma, testicularcancer (e.g., seminoma, testicular embryonal carcinoma), thyroid cancer(e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma(PTC), medullary thyroid cancer), and Waldenström's macroglobulinemia.

In some embodiments, provided herein are methods of treating a hememalignancy in a subject comprising administering to said subject atherapeutically effective amount of a compound provided herein, or apharmaceutically acceptable salt, ester, prodrug, solvate, hydrate orderivative thereof. In some embodiments, the heme malignancy is amyeloid malignancy. Exemplary mycloid malignancies that can be treatedusing the compounds provided herein include: leukemia (e.g., acutemycloid leukemia (AML) or chronic myelocytic leukemia (CML));myelodysplastic syndromes (MDS) (e.g., high grade MDS or low grade MDS);myeloproliferative disease (MPD) (e.g., essential thrombocytosis (ET),myelofibrosis (MF), polycythemia vera (PV), or chronic myelomonocyticleukemia (CMML)), and mast cell disorders.

In some embodiments, the heme malignancy is a lymphoid malignancy, e.g.,a lymphoma. Exemplary lymphomas that can be treated using the compoundsprovided herein include Hodgkin's lymphoma, non-Hodgkin's lymphoma(e.g., B-cell or T-cell), leukemia (e.g., acute lymphocytic leukemia(ALL) or chronic lymphocytic leukemia (CLL)), and post transplantationallymphoproliferative disorders (PLDs). Exemplary B-cell lymphomasinclude: diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma,and indolent non-Hodgkin's lymphoma (iNHL). Exemplary T-cell lymphomasinclude peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma(CTCL). Exemplary acute lymphocytic leukemias (ALLs) include T-cell ALLand B-cell ALL. Exemplary PLDs include multiple myeloma, Waldenström'sPLD, and amyloid PLD.

In other embodiments, the compounds and compositions provided herein canbe used for preventing a PI3K-mediated cancer, in a subject having, orat risk of having, the PI3K-mediated cancer. In one embodiment, thecompounds and compositions provided herein can be used as achemopreventive agent, e.g., as an agent that inhibits, delays, orreverses the development of a PI3K-mediated cancer. Such a role issupported, at least in pan, by an extensive body showing the effects ofanti-inflammatory agents, such as COX-2 inhibitors, as chemopreventiveagents to reduce or inhibit the development of a cancer, including coloncancer, among others. Since both COX-2 inhibitors and PI3K inhibitorshave broad anti-inflammatory activity, PI3K inhibition is expected tohave chemopreventive activity in reducing or inhibiting the developmentof a variety of cancers.

In certain embodiments, a method of treating or preventing a relapseand/or a recurrence of a PI3K-mediated cancer (e.g., a PI3K-mediatedcancer as described herein) in a subject is provided. The methodincludes administering to the subject a PI3K inhibitor, e.g., one ormore PI3K inhibitors as described herein, in an amount sufficient toreduce or inhibit the tumor or cancer re-growth or relapse, in thesubject. In certain embodiments, the subject is a patient who isundergoing, or has undergone, cancer therapy (e.g., treatment with otheranti-cancer agents, surgery and/or radiation). The PI3K inhibitor can beadministered before treatment, concurrently with treatment,post-treatment, with other cancer therapies; or during remission of thecancer. The inhibition of relapse or recurrence need not be absolute, aslong as the treatment or prevention delays (e.g., by a week, month,year) the relapse and/or recurrence, or reduces or retards the re-growth(e.g., by at least about 10%, about 20%, about 30%, about 40%, about 50%or more) of the PI3K-mediated cancer (e.g., compared to a subject nottreated with the PI3K inhibitor).

Thus, in one embodiment, a method of extending relapse free survival ina subject with a cancer who is undergoing, or has undergone, cancertherapy by administering a therapeutically effective amount of a PI3Kinhibitor to the subject is disclosed. “Relapse free survival,” asunderstood by those skilled in the art, is the length of time followinga specific point of cancer treatment during which there is noclinically-defined relapse in the cancer. In some embodiments, the PI3Kinhibitor is administered concurrently with the cancer therapy. In otherembodiments, the PI3K inhibitor is administered sequentially (in anyorder) with the cancer therapy. In instances of concurrentadministration, the PI3K inhibitor can continue to be administered afterthe cancer therapy has ceased. In other embodiments, the PI3K inhibitoris administered after cancer therapy has ceased (e.g., with no period ofoverlap with the cancer treatment). The PI3K inhibitor can beadministered immediately after cancer therapy has ceased, or there canbe a gap in time (e.g., up to a few hours, about a day, about a week,about a month, about six months, or a year) between the end of cancertherapy and the administration of the PI3K inhibitor. Treatment with thePI3K inhibitor can continue for as long as relapse-free survival ismaintained (e.g., up to about a day, about a week, about a month, aboutsix months, about a year, about two years, about three years, about fouryears, about five years, or longer).

Also provided herein is a method of treating diabetes in a mammalcomprising administering to said mammal a therapeutically effectiveamount of a compound provided herein, or a pharmaceutically acceptablesalt, ester, prodrug, solvate, hydrate or derivative thereof.

In addition, the compounds described herein can be used to treat acne.In certain embodiments, the inflammatory condition and/or immunedisorder is a skin condition. In some embodiments, the skin condition ispruritus (itch), psoriasis, eczema, burns or dermatitis. In certainembodiments, the skin condition is psoriasis. In certain embodiments,the skin condition is pruritis.

In addition, the compounds described herein can be used for thetreatment of arteriosclerosis, including atherosclerosis.Arteriosclerosis is a general term describing any hardening of medium orlarge arteries. Atherosclerosis is a hardening of an artery specificallydue to an atheromatous plaque.

In some embodiments, provided herein is a method of treating acardiovascular disease in a subject that comprises administering to saidsubject a therapeutically effective amount of a compound as disclosedherein, or a pharmaceutically acceptable form (e.g., pharmaceuticallyacceptable salts, hydrates, solvates, chelates, non-covalent complexes,isomers, prodrugs, and isotopically labeled derivatives) thereof.Examples of cardiovascular conditions include, but are not limited to,atherosclerosis, restenosis, vascular occlusion and carotid obstructivedisease.

In certain embodiments, the inflammatory disorder and/or the immunedisorder is a gastrointestinal disorder. In some embodiments, thegastrointestinal disorder is selected from gastrointestinal disorder(e.g., selected from peptic ulcers, regional enteritis, diverticulitis,gastrointestinal bleeding, eosinophilic gastrointestinal disorders(e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilicgastroenteritis, eosinophilic colitis), gastritis, diarrhea,gastroesophageal reflux disease (GORD, or its synonym GERD),inflammatory bowel disease (IBD) (e.g., Crohn's disease, ulcerativecolitis, collagenous colitis, lymphocytic colitis, ischaemic colitis,diversion colitis, Behcet's syndrome, indeterminate colitis) andinflammatory bowel syndrome (IBS)). In certain embodiments, thegastrointestinal disorder is inflammatory bowel disease (IBD).

Further, the compounds described herein, or a pharmaceuticallyacceptable form (e.g., pharmaceutically acceptable salts, hydrates,solvates, chelates, non-covalent complexes, isomers, prodrugs, andisotopically labeled derivatives) thereof, can be used for the treatmentof glomerulonephritis. Glomerulonephritis is a primary or secondaryautoimmune renal disease characterized by inflammation of the glomeruli.It can be asymptomatic, or present with hematuria and/or proteinuria.There are many recognized types, divided in acute, subacute or chronicglomerulonephritis. Causes can be infectious (bacterial, viral orparasitic pathogens), autoimmune, or paraneoplastic.

In some embodiments, provided herein are compounds, or apharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, chelates, non-covalent complexes, isomers,prodrugs, and isotopically labeled derivatives) thereof, orpharmaceutical compositions as disclosed herein, for the treatment ofmultiorgan failure. Also provided herein are compounds, or apharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, chelates, non-covalent complexes, isomers,prodrugs, and isotopically labeled derivatives) thereof, orpharmaceutical compositions as disclosed herein, for the treatment ofliver diseases (including diabetes), gall bladder disease (includinggallstones), pancreatitis or kidney disease (including proliferativeglomerulonephritis and diabetes-induced renal disease) or pain in asubject.

In some embodiments, provided herein are compounds, or apharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, chelates, non-covalent complexes, isomers,prodrugs, and isotopically labeled derivatives) thereof, orpharmaceutical compositions as disclosed herein, for the prevention ofblastocyte implantation in a subject.

In some embodiments, provided herein are compounds, or apharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, chelates, non-covalent complexes, isomers,prodrugs, and isotopically labeled derivatives) thereof, orpharmaceutical compositions as disclosed herein, for the treatment ofdisorders involving platelet aggregation or platelet adhesion,including, but not limited to Idiopathic thrombocytopenic purpura,Bemard-Soulier syndrome, Glanzmann's thrombasthenia, Scott's syndrome,von Willebrand disease, Hermansky-Pudlak Syndrome, and Gray plateletsyndrome.

In some embodiments, compounds, or a pharmaceutically acceptable form(e.g., pharmaceutically acceptable salts, hydrates, solvates, chelates,non-covalent complexes, isomers, prodrugs, and isotopically labeledderivatives) thereof, or pharmaceutical compositions as disclosedherein, are provided for treating a disease which is skeletal muscleatrophy, skeletal or muscle hypertrophy. In some embodiments, providedherein are compounds, or a pharmaceutically acceptable form (e.g.,pharmaceutically acceptable salts, hydrates, solvates, chelates,non-covalent complexes, isomers, prodrugs, and isotopically labeledderivatives) thereof, or pharmaceutical compositions as disclosedherein, for the treatment of disorders that include, but are not limitedto, cancers as discussed herein, transplantation-related disorders(e.g., lowering rejection rates, graft-versus-host disease, etc.),muscular sclerosis (MS), allergic disorders (e.g., arthritis, allergicencephalomyelitis) and other immunosuppressive-related disorders,metabolic disorders (e.g., diabetes), reducing intimal thickeningfollowing vascular injury, and misfolded protein disorders (e.g.,Alzheimer's Disease, Gaucher's Disease, Parkinson's Disease,Huntington's Disease, cystic fibrosis, macular degeneration, retinitispigmentosa, and prion disorders) (as mTOR inhibition can alleviate theeffects of misfolded protein aggregates). The disorders also includehamartoma syndromes, such as tuberous sclerosis and Cowden Disease (alsotermed Cowden syndrome and multiple hamartoma syndrome).

In other embodiments, the compounds described herein can be used for thetreatment of bursitis, lupus, acute disseminated encephalomyelitis(ADEM), addison's disease, antiphospholipid antibody syndrome (APS),aplastic anemia, autoimmune hepatitis, coeliac disease, crohn's disease,diabetes mellitus (type 1), goodpasture's syndrome, graves' disease,guillain-barré syndrome (GBS), hashimoto's disease, inflammatory boweldisease, lupus erythematosus, myasthenia gravis, opsoclonus myoclonussyndrome (OMS), optic neuritis, ord's thyroiditis, ostheoarthritis,uveoretinitis, pemphigus, polyarthritis, primary biliary cirrhosis,reiter's syndrome, takayasu's arteritis, temporal arteritis, warmautoimmune hemolytic anemia, wegener's granulomatosis, alopeciauniversalis, chagas' disease, chronic fatigue syndrome, dysautonomia,endometriosis, hidradenitis suppurativa, interstitial cystitis,neuromyotonia, sarcoidosis, scleroderma, ulcerative colitis, vitiligo,vulvodynia, appendicitis, arteritis, arthritis, blepharitis,bronchiolitis, bronchitis, cervicitis, cholangitis, cholecystitis,chorioamnionitis, colitis, conjunctivitis, cystitis, dacryoadenitis,dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis,epicondylitis, epididymitis, fasciitis, fibrositis, gastritis,gastroenteritis, gingivitis, hepatitis, hidradenitis, ileitis, iritis,laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis,nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis,pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis,pleuritis, phlebitis, pneumonitis, proctitis, prostatitis,pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis,tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, or vulvitis.

In other embodiments, the compounds provided herein can be used for thetreatment of Perennial allergic rhinitis, Mesenteritis, Peritonitis,Acrodematitis, Angiodermatitis, Atopic dermatitis, Contact dermatitis,Eczema, Erythema multiforme, Intertrigo, Stevens Johnson syndrome, Toxicepidermal necrolysis, Skin allergy, Severe allergicreaction/anaphylaxis, Allergic granulomatosis, Wegener granulomatosis,Allergic conjunctivitis, Chorioretinitis, Conjunctivitis, Infectiouskeratoconjunctivitis, Keratoconjunctivitis, Ophthalmia neonatorum,Trachoma, Uveitis, Ocular inflammation, Blepharoconjunctivitis,Mastitis, Gingivitis, Pericoronitis, Pharyngitis, Rhinopharyngitis,Sialadenitis, Musculoskeletal system inflammation, Adult onset Stillsdisease, Behcets disease, Bursitis, Chondrocalcinosis, Dactylitis, Feltysyndrome, Gout, Infectious arthritis, Lyme disease, Inflammatoryosteoarthritis, Periarthritis, Reiter syndrome, Ross River virusinfection, Acute Respiratory, Distress Syndrome, Acute bronchitis, Acutesinusitis, Allergic rhinitis, Asthma, Severe refractory asthma,Pharyngitis, Pleurisy, Rhinopharyngitis, Seasonal allergic rhinitis,Sinusitis, Status asthmaticus, Tracheobronchitis, Rhinitis, Serositis,Meningitis, Neuromyelitis optica, Poliovirus infection, Alport syndrome,Balanitis, Epididymitis, Epididymo orchitis, Focal segmental,Glomerulosclerosis, Glomerulonephritis, IgA Nephropathy (Berger'sDisease), Orchitis, Parametritis, Pelvic inflammatory disease,Prostatitis, Pyelitis, Pyelocystitis, Pyelonephritis, Wegenergranulomatosis, Hyperuricemia, Aortitis, Arteritis, Chylopericarditis,Dressier syndrome, Endarteritis, Endocarditis, Extracranial temporalarteritis, HIV associated arteritis, Intracranial temporal arteritis,Kawasaki disease, Lymphangiophlebitis, Mondor disease, Periarteritis, orPericarditis.

In other embodiments, the compounds provided herein are used for thetreatment of Autoimmune hepatitis, Jejunitis, Mesenteritis, Mucositis,Non alcoholic steatohepatitis, Non viral hepatitis, Autoimmunepancreatitis, Perihepatitis, Peritonitis, Pouchitis, Proctitis,Pseudomembranous colitis, Rectosigmoiditis, Salpingoperitonitis,Sigmoiditis, Steatohepatitis, Ulcerative colitis, Churg Strausssyndrome, Ulcerative proctitis, Irritable bowel syndrome,Gastrointestinal inflammation, Acute enterocolitis, Anusitis, Balsernecrosis, Cholecystitis, Colitis, Crohns disease, Diverticulitis,Enteritis, Enterocolitis, Enterohepatitis, Eosinophilic esophagitis,Esophagitis, Gastritis, Hemorrhagic enteritis, Hepatitis, Hepatitisvirus infection, Hepatocholangitis, Hypertrophic gastritis, Ileitis,Ileocecitis, Sarcoidosis, Inflammatory bowel disease, Ankylosingspondylitis, Rheumatoid arthritis, Juvenile rheumatoid arthritis,Psoriasis, Psoriatic arthritis. Lupus (cutaneous/systemic/nephritis),AIDS, Agammaglobulinemia, AIDS related complex, Brutons disease, ChediakHigashi syndrome, Common variable immunodeficiency, DiGeorge syndrome,Dysgammaglobulinemia, Immunoglobulindeficiency, Job syndrome, Nezelofsyndrome, Phagocyte bactericidal disorder, Wiskott Aldrich syndrome,Asplenia, Elephantiasis. Hypersplenism, Kawasaki disease,Lymphadenopathy, Lymphedema, Lymphocele, Nonne Milroy Meige syndrome,Spleen disease, Splenomegaly, Thymoma, Thymus disease, Perivasculitis,Phlebitis, Pleuropericarditis, Polyarteritis nodosa, Vasculitis,Takayasus arteritis, Temporal arteritis, Thromboangiitis,Thromboangiitis obliterans, Thromboendocarditis, Thrombophlebitis, orCOPD.

In some embodiments, provided herein are methods of treating aninflammatory or autoimmune disease in a subject comprising administeringto said subject a therapeutically effective amount of a compoundprovided herein, or a pharmaceutically acceptable salt, ester, prodrug,solvate, hydrate or derivative thereof. In some embodiments, theinflammatory or autoimmune disease includes asthma, rheumatoidarthritis, Crohn's disease, lupus, and multiple sclerosis.

In some embodiments, the inflammatory or autoimmune disease includes:idiopathic thrombocytopenic purpura; anemia, e.g., aplastic anemia;lupus, e.g., cutaneous lupus erythematosus; and pemphigoid, e.g., skinblistering bullous pemphigoid.

Also provided herein is a method of treating a cardiovascular disease ina mammal comprising administering to said mammal a therapeuticallyeffective amount of a compound provided herein, or a pharmaceuticallyacceptable salt, ester, prodrug, solvate, hydrate, or derivativethereof. Examples of cardiovascular conditions include, but are notlimited to, atherosclerosis, restenosis, vascular occlusion and carotidobstructive disease.

In another embodiment, provided herein are methods for disrupting thefunction of a leukocyte or disrupting a function of an osteoclast. Inone embodiment, the method comprises contacting the leukocyte or theosteoclast with a function disrupting amount of a compound providedherein.

In another embodiment, provided herein are methods for treatingophthalmic disease by administering a compound provided herein or apharmaceutical composition provided herein to the eye of a subject.

V. Combination Treatment

Also provided herein are methods for combination therapies in which anagent known to modulate other pathways, or other components of the samepathway, or even overlapping sets of target enzymes are used incombination with a compound provided herein, or a pharmaceuticallyacceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.In one embodiment, such therapy includes, but is not limited to thecombination of the subject compound with chemotherapeutic agents,therapeutic antibodies, and radiation treatment, to provide asynergistic or additive therapeutic effect.

In one embodiment, the compounds or pharmaceutical compositions providedherein can present synergistic or additive efficacy when administered incombination with agents that inhibit IgE production or activity. Suchcombination can reduce the undesired effect of high level of IgEassociated with the use of one or more P3Kδ inhibitors, if such effectoccurs. In some embodiments, this can be particularly useful intreatment of autoimmune and inflammatory disorders (AIID) such asrheumatoid arthritis. Additionally, without being limited by aparticular theory, the administration of PI3Kδ or PI3Kδ/γ inhibitorsprovided herein in combination with inhibitors of mTOR can also exhibitsynergy through enhanced inhibition of the P3K pathway.

In another embodiment, provided herein is a combination treatment of adisease associated with PI3Kδ comprising administering to a subject aPI3Kδ inhibitor and an agent that inhibits IgE production or activity.Other exemplary P3Kδ inhibitors are applicable and they are describedin, e.g., U.S. Pat. No. 6,800,620, incorporated by reference. In someembodiments, such combination treatment is particularly useful fortreating autoimmune and inflammatory diseases (AIID), including but notlimited to, rheumatoid arthritis.

Agents that inhibit IgE production are known in the art, and theyinclude, but are not limited to, one or more of TEI-9874,2-(4-(6-cyclohexyloxy-2-naphtyloxy)phenylacetamide)benzoic acid,rapamycin, rapamycin analogs (i.e., rapalogs), TORC1 inhibitors, TORC2inhibitors, and any other compounds that inhibit mTORC1 and mTORC2.Agents that inhibit IgE activity include, for example, anti-IgEantibodies, such as, for example, Omalizumab and TNX-901.

For treatment of autoimmune diseases, the compounds or pharmaceuticalcompositions provided herein can be used in combination with commonlyprescribed drugs, including but not limited to, Enbrel®, Remicade®,Humima®, Avonex®, and Rebif®. For treatment of respiratory diseases, thecompounds or pharmaceutical compositions provided herein can beadministered in combination with commonly prescribed drugs, includingbut not limited to, Xolair®, Advair®, Singulair®, and Spiriva®.

In one embodiment, the compounds provided herein can be formulated oradministered in conjunction with other agents that act to relieve thesymptoms of inflammatory conditions, such as encephalomyelitis, asthma,and the other diseases described herein. These agents include, but arenot limited to, non-steroidal anti-inflammatory drugs (NSAIDs), e.g.,acetylsalicylic acid; ibuprofen; naproxen; indomethacin; nabumetone; andtolmetin. In some embodiments, corticosteroids are used to reduceinflammation and suppress activity of the immune system. For example,one commonly prescribed drug of this type is Prednisone. Chloroquine(Aralen®) or hydroxychloroquine (Plaquenil®) can also be very useful insome individuals with lupus. They are often prescribed for skin andjoint symptoms of lupus. Azathioprine (Imuran) and cyclophosphamide(CYTOXAN™) suppress inflammation and tend to suppress the immune system.Other agents, e.g., methotrexate and cyclosporin can be used to controlthe symptoms of lupus. Anticoagulants are employed to prevent blood fromclotting rapidly. For example, they range from aspirin at very low dosewhich prevents platelets from sticking, to heparin/coumadin. Othercompounds used in the treatment of lupus include belimumab (Benlysta®).

In another embodiment, provided herein is a pharmaceutical compositionfor inhibiting abnormal cell growth in a mammal, comprising an amount ofa compound provided herein, or a pharmaceutically acceptable salt,ester, prodrug, solvate, hydrate or derivative thereof, in combinationwith an amount of an anti-cancer agent (e.g., a biotherapeutic orchemotherapeutic agent). Many chemotherapeutics are presently known inthe art and can be used in combination with the compounds providedherein. Other cancer therapies, that can also be used in combinationwith the compounds provided herein, include, but are not limited to,surgery, surgical treatments, and radiation therapy.

In some embodiments, the chemotherapeutic agent is selected from thegroup consisting of mitotic inhibitors, alkylating agents,anti-metabolites, intercalating antibiotics, growth factor inhibitors,cell cycle inhibitors, enzymes, topoisomerase inhibitors, biologicalresponse modifiers, anti-hormones, angiogenesis inhibitors, andanti-androgens. Non-limiting examples of anti-cancer agents include,e.g., chemotherapeutic agents, cytotoxic agents, and non-peptide smallmolecules such as Gleevec® (Imatinib Mesylate), Velcade® (bortezomib),CASODEX™ (bicalutamide), Iressa™ (gefitinib), and Adriamycin as well asa host of chemotherapeutic agents. Non-limiting examples ofchemotherapeutic agents include, e.g., alkylating agents such asthiotepa and cyclosphosphamide (CYTOXAN™); alkyl sulfonates such asbusulfan, improsulfan and piposulfan; aziridines such as benzodopa,carboquone, meturedopa, and uredopa; ethylenimines and methylamelaminesincluding altretamine, triethylenemelamine, trietylenephosphoramide,triethylenethiophosphaoramide and trimethylolomelamine; nitrogenmustards such as chlorambucil, chlomaphazine, cholophosphamide,estramustine, ifosfamide, mechlorethamine, mechlorethamine oxidehydrochloride, melphalan, novembichin, phenesterine, prednimustine,trofosfamide, uncial mustard; nitrosureas such as carmustine,chlorozotocin, fotemustine, lomustine, nimustine, ranimustine;antibiotics such as aclacinomysins, actinomycin, authramycin, azaserine,bleomycins, cactinomycin, calicheamicin, carabicin, carminomycin,carzinophilin, CASODE™, chromomycins, dactinomycin, daunorubicin,detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin,esorubicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid,nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin,quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexateand 5-fluorouracil (5-FU); folic acid analogues such as denopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine,androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; anti-adrenals such as aminoglutethimide,mitotane, trilostane; folic acid replenisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine;bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elformithine; elliptinium acetate; etoglucid; galliumnitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone;mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinicacid; 2-ethylhydrazide; procarbazine; PSK.R™; razoxane; sizofiran;spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-trichlorotriethyla-mine; urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxanes, e.g.,paclitaxel (TAXOL™, Bristol-Myers Squibb Oncology, Princeton, N.J.) anddocetaxel (TAXOTERE®, Rhone-Poulenc Rorer, Antony, France); retinoicacid; esperamicins; and capecitabine; and pharmaceutically acceptablesalts, solvates, or derivatives of any of the above. Also included assuitable chemotherapeutic cell conditioners are anti-hormonal agentsthat act to regulate or inhibit hormone action on tumors such asanti-estrogens including, for example, tamoxifen (Novaldex™),raloxifene, aromatase inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen,trioxifene, keoxifene, LY 17018, onapristone, and toremifene (Fareston);and anti-androgens such as flutamide, nilutamide, bicalutamide,leuprolide, and goserelin; chloranbucil; gemcitabine; 6-thioguanine;mercaptopurine; methotrexate; platinum analogs such as cisplatin andcarboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide;mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine;novantrone; teniposide; daunomycin; aminopterin; Xcloda®; ibandronate;camptothecin-11 (CPT-11); topoisomerase inhibitor RFS 2000; anddifluoromethylomithine (DMFO). In some embodiments, the compounds orpharmaceutical composition provided herein can be used in combinationwith commonly prescribed anti-cancer drugs, such as, e.g., Hereeptin®,Avastin®, Erbitux®, Rituxan®, Taxol®, Arimidex®, Taxotere®, andVelcade®.

Non-limiting examples are chemotherapeutic agents, cytotoxic agents, andnon-peptide small molecules include ABVD, Avicine, Abagovomab, Acridinecarboxamide, Adecatumumab, 17-N-Allylamino-17-demethoxygeldanamycin,Alpharadin, Alvocidib, 3-Aminopyridine-2-carboxaldehydethiosemicarbazone, Amonafide, Anthracenedione, Anti-CD22 immunotoxins,Antineoplastic, Antitumorigenic herbs, Apaziquone®, Atiprimod,Azathioprine, Belotecan, Bendamustine, BIBW 2992, Biricodar,Brostallicin, Bryostatin, Buthionine sulfoximine, CBV (chemotherapy),Calyculin, Crizotinib, cell-cycle nonspecific antineoplastic agents,Dichloroacetic acid, Discodermolide, Elsamitrucin, Enocitabine,Epothilone, Eribulin, Everolimus, Exatecan, Exisulind, Ferruginol,Forodesine, Fosfestrol, ICE chemotherapy regimen, IT-101, lmexon,Imiquimod, Indolocarbazole, Irofulven, Laniquidar, Larotaxel,Lenalidomide, Lucanthone, Lurtotecan, Mafosfamide, Mitozolomide,Nafoxidine, Nedaplatin, Olaparib, Ortataxel, PAC-1, Pawpaw, Pixantrone,Proteasome inhibitor, Rebeccamycin, Resiquimod, Rubitecan, SN-38,Salinosporamide A, Sapacitabine, Stanford V, Swainsonine, Talaporfin,Tariquidar, Tegafur-uracil, Temodar®, Tesetaxel, Triplatin tetranitrate,Tris(2-chloroethyl)amine, Troxacitabine, Uramustine, Vadimezan,Vinflunine, ZD6126, and Zosuquidar.

In some embodiments, the chemotherapeutic is selected from hedgehoginhibitors including, but not limited to IPI-926 (See U.S. Pat. No.7,812,164). Other suitable hedgehog inhibitors include, for example,those described and disclosed in U.S. Pat. No. 7,230,004, U.S. PatentApplication Publication No. 2008/0293754, U.S. Patent ApplicationPublication No. 2008/0287420, and U.S. Patent Application PublicationNo. 2008/0293755, the entire disclosures of which are incorporated byreference herein. Examples of other suitable hedgehog inhibitors includethose described in U.S. Patent Application Publication Nos. US2002/0006931, US 2007/0021493 and US 2007/0060546, and InternationalApplication Publication Nos. WO 2001/19800, WO 2001/26644, WO2001/27135, WO 2001/49279, WO 2001/74344, WO 2003/011219, WO2003/088970, WO 2004/020599, WO 2005/013800, WO 2005/033288, WO2005/032343, WO 2005/042700, WO 2006/028958, WO 2006/050351, WO2006/078283, WO 2007/054623, WO 2007/059157, WO 2007/120827, WO2007/131201, WO 2008/070357, WO 2008/110611, WO 2008/112913, and WO2008/131354. Additional examples of hedgehog inhibitors include, but arenot limited to, GDC-0449 (also known as RG3616 or vismodegib) describedin, e.g., Von Hoff D. et al., N. Engl. J. Med. 2009; 361(12):1164-72;Robarge K. D. et al., Bioorg Med Chem Lett. 2009; 19(19):5576-81; Yaueh,R. L. et al. (2009) Science 326: 572-574; Sciencexpress: 1-3(10.1126/science.1179386); Rudin, C. et al. (2009) New England J ofMedicine 361-366 (10.1056/nejma0902903); BMS-833923 (also known asXL139) described in, e.g., in Siu L. et al., J. Clin. Oncol. 2010;28:15s (suppl; abstr 2501); and National Institute of Health ClinicalTrial Identifier No. NCT006701891; LDE-225 described, e.g., in Pan S, etal., ACS Med. Chem. Lett., 2010; 1(3): 130-134; LEQ-506 described, e.g.,in National Institute of Health Clinical Trial Identifier No.NCT01106508; PF-04449913 described, e.g., in National Institute ofHealth Clinical Trial Identifier No. NCT00953758; Hedgehog pathwayantagonists disclosed in U.S. Patent Application Publication No.2010/0286114; SMOi2-17 described, e.g., U.S. Patent ApplicationPublication No. 2010/0093625; SANT-1 and SANT-2 described, e.g., inRominger C. M. et al., J. Pharmacol. Exp. Ther. 2009; 329(3):995-1005;l-piperazinyl-4-arylphthalazines or analogues thereof, described inLucas B. S. et al., Bioorg. Med Chem. Lett. 2010; 20(12):3618-22.

Other chemotherapeutic agents include, but are not limited to,anti-estrogens (e.g., tamoxifen, raloxifene, and megestrol), LHRHagonists (e.g., goserelin and leuprolide), anti-androgens (e.g.,flutamide and bicalutamide), photodynamic therapies (e.g., verteporfin(BPD-MA), phthalocyanine, photosensitizer Pc4, and demethoxy-hypocrellinA (2BA-2-DMHA)), nitrogen mustards (e.g., cyclophosphamide, ifosfamide,trofosfamide, chlorambucil, estramustine, and melphalan), nitrosoureas(e.g., carmustine (BCNU) and lomustine (CCNU)), alkylsulphonates (e.g.,busulfan and treosulfan), triazenes (e.g., dacarbazine, temozolomide),platinum containing compounds (e.g., cisplatin, carboplatin,oxaliplatin), vinca alkaloids (e.g., vincristine, vinblastine,vindesine, and vinorelbine), taxoids (e.g., paclitaxel or a paclitaxelequivalent such as nanoparticle albumin-bound paclitaxel (Abraxane),docosahexaenoic acid bound-paclitaxel (DHA-paclitaxel, Taxoprexin®),polyglutamate bound-paclitaxel (PG-paclitaxel, paclitaxel poliglumex,CT-2103, XYOTAX™), the tumor-activated prodrug (TAP) ANG1005 (Angiopep-2bound to three molecules of paclitaxel), paclitaxel-EC-1 (paclitaxelbound to the crbB2-recognizing peptide EC-1), and glucose-conjugatedpaclitaxel, e.g., 2′-paclitaxel methyl 2-glucopyranosyl succinate;docetaxel, taxol), epipodophyllins (e.g., etoposide, etoposidephosphate, teniposide, topotecan, 9-aminocamptothecin, camptoirinotecan,irinotecan, crisnatol, mytomycin C), anti-metabolites, DHFR inhibitors(e.g., methotrexate, dichloromethotrexate, trimetrexate, edatrexate),IMP dehydrogenase inhibitors (e.g., mycophenolic acid, tiazofurin,ribavirin, and EICAR), ribonuclotide reductase inhibitors (e.g.,hydroxyurea and deferoxamine), uracil analogs (e.g., 5-fluorouracil(5-FU), floxuridine, doxifluridine, ratitrexed, tegafur-uracil,capecitabine), cytosine analogs (e.g., cytarabine (am C), cytosinearabinoside, and fludarabine), purine analogs (e.g., mercaptopurine andThioguanine), Vitamin D3 analogs (e.g., EB 1089, CB 1093, and KH 1060),isoprenylation inhibitors (e.g., lovastatin), dopaminergic neurotoxins(e.g., 1-methyl-4-phenylpyridinium ion), cell cycle inhibitors (e.g.,staurosporine), actinomycin (e.g., actinomycin D, dactinomycin),bleomycin (e.g., bleomycin A2, bleomycin B2, peplomycin), anthracycline(e.g., daunorubicin, doxorubicin, pegylated liposomal doxorubicin,idarubicin, epirubicin, pirarubicin, zorubicin, mitoxantrone), MDRinhibitors (e.g., verapamil), Ca²⁺ ATPase inhibitors (e.g.,thapsigargin), imatinib, thalidomide, lenalidomide, tyrosine kinaseinhibitors (e.g., axitinib (AG013736), bosutinib (SKI-606), cediranib(RECENTIN™, AZD2171), dasatinib (SPRYCEL®, BMS-354825), criotinib(TARCEVA®), gefitinib (IRESSA®), imatinib (Gleevee®, CGP571488,STI-571), lapatinib (TYKERB®, TYVERB®), lestaurtinib (CEP-701),ncratinib (HKI-272), nilotinib (TASIGNA®), scmaxanib (semaxinib,SU5416), sunitinib (SUTENT®, SU11248), toccranib (PALLADIA®), vandetanib(ZACTMA®, ZD6474), vatalanib (PTK787, PTK/ZK), trastuzumab (HERCEPTIN®),bevacizumab (AVASTIN®), rituximab (RITUXA®), cetuximab (ERBITU®),panitumumab (VECTIBIX®), ranibizumab (Luccntis®), nilotinib (TASIGNA®),sorafenib (NEXAVAR®), everolimus (AFINITOR®), alcmtuzumab (CAMPATH®),gemtuzumab ozogamicin (MYLOTARG®), temsirolimus (TORISEL®), ENMD-2076,PCI-32765, AC220, dovitinib lactate (TK1258, CHIR-258), BIBW 2992(TOVOK™), SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607,ABT-869, MP470, BIBF 1120 (VARGATEF®), AP24534, JNJ-26483327, MGCD265,DCC-2036, BMS-690154, CEP-11981, tivozanib (AV-951), OSI-930, MM-121,XL-184, XL-647, and/or XL228), proteasome inhibitors (e.g., bortezomib(Veleade®), mTOR inhibitors (e.g., rapamycin, temsirolimus (CCI-779),everolimus (RAD-001), ridaforolimus, AP23573 (Ariad). AZD8055(AstraZeneca), BEZ235 (Novartis), BGT226 (Norvartis), XL765 (SanofiAventis), PF4691502 (Pfizer), GDC0980 (Genetech). SF1126 (Semafoe) andOSI-027 (OSI)), oblimersen, gemcitabine, carminomycin, leucovorin,pemetrexed, cyclophosphamide, dacarbazine, procarbazine, prednisolone,dexamethasone, camptothecin, plicamycin, asparaginase, aminopterin,methopterin, porfiromycin, melphalan, leurosidine, leurosine,chlorambucil, trabectedin, procarbazine, discodermolide, caminomycin,aminopterin, and hexamethyl melamine.

Exemplary biotherapeutic agents include, but are not limited to,interferons, cytokines (e.g., tumor necrosis factor, interferon α,interferon γ), vaccines, hematopoietic growth factors, monoclonalserotherapy, immunostimulants and/or immunodulatory agents (e.g., IL-1,2, 4, 6, or 12), immune cell growth factors (e.g., GM-CSF) andantibodies (e.g., Herceptin®, (trastuzumab), T-DM1, AVASTIN®(bevacizumab), ERBITUX® (cetuximab), Vectibix® (panitumumab), Rituxan®(rituximab), and Bexxar® (tositumomab)).

In some embodiments, the chemotherapeutic is selected from HSP90inhibitors. The HSP90 inhibitor can be a geldanamycin derivative, e.g.,a benzoquinone or hygroquinone ansamycin HSP90 inhibitor (e.g., IPI-493and/or IPI-504). Non-limiting examples of HSP90 inhibitors includeIPI-493, IPI-504, 17-AAG (also known as tanespimycin or CNF-1010),BIIB-021 (CNF-2024), BIIB-028, AUY-922 (also known as VER-49009),SNX-5422, STA-9090, AT-13387, XL-888, MPC-3100, CU-0305, 17-DMAG,CNF-1010, Macbecin (e.g., Macbecin I, Macbecin II), CCT-018159,CCT-129397, PU-H71, or PF-04928473 (SNX-2112).

In some embodiments, the chemotherapeutic is selected from PI3Kinhibitors (e.g., including those PI3K inhibitors disclosed herein andthose PI3K inhibitors not disclosed herein). In some embodiment, thePI3K inhibitor is an inhibitor of delta and gamma isoforms of PI3K. Insome embodiments, the PI3K inhibitor is an inhibitor of alpha isoformsof P3K. In other embodiments, the PI3K inhibitor is an inhibitor of oneor more alpha, beta, delta and gamma isoforms of PI3K. Exemplary PI3Kinhibitors that can be used in combination are described in, e.g., WO09/088990, WO 09/088086, WO 2011/008302, WO 2010/036380, WO 2010/006086,WO 09/114870, WO 05/113556; US 2009/0312310, and US 2011/0046165.Additional PI3K inhibitors that can be used in combination with thepharmaceutical compositions include but are not limited to, GSK 2126458,GDC-0980, GDC-0941, Sanofi XL147, XL756, XL147, PF46915032, BKM 120,CAL-101, CAL 263, SF1126, PX-886, and a dual PI3K inhibitor (e.g.,Novartis BEZ235). In one embodiment, the PI3K inhibitor is anisoquinolinone.

Also provided herein is a method for using the compounds as disclosedherein, or a pharmaceutically acceptable form (e.g., pharmaceuticallyacceptable salts, hydrates, solvates, chelates, non-covalent complexes,isomers, prodrugs, and isotopically labeled derivatives) thereof, orpharmaceutical compositions as disclosed herein in combination withradiation therapy in inhibiting abnormal cell growth or treating thehyperproliferative disorder in a mammal. Techniques for administeringradiation therapy are known in the art, and these techniques can be usedin the combination therapy described herein. In such combinationtherapy, the compound provided herein can be administered as describedherein.

In one embodiment, radiation therapy can be administered through one ofseveral methods, or a combination of methods, including withoutlimitation, external-beam therapy, internal radiation therapy, implantradiation, stereotactic radiosurgery, systemic radiation therapy,radiotherapy and permanent or temporary interstitial brachytherapy. Theterm “brachytherapy,” as used herein, refers to radiation therapydelivered by a spatially confined radioactive material inserted into thebody at or near a tumor or other proliferative tissue disease site. Theterm is intended without limitation to include exposure to radioactiveisotopes (e.g., At-211, 1-131, 1-125, Y-90, Rc-186, Rc-188, Sm-153,Bi-212, P-32, and radioactive isotopes of Lu). Suitable radiationsources for use as a cell conditioner described herein include bothsolids and liquids. By way of non-limiting example, the radiation sourcecan be a radionuclide, such as 1-125, 1-131, Yb-169, or Ir-192 as asolid source, 1-125 as a solid source, or other radionuclides that emitphotons, beta particles, gamma radiation, or other therapeutic rays. Theradioactive material can also be a fluid made from any solution ofradionuclide(s), e.g., a solution of 1-125 or 1-131, or a radioactivefluid can be produced using a slurry of a suitable fluid containingsmall particles of solid radionuclides, such as Au-198, or Y-90.Moreover, the radionuclide(s) can be embodied in a gel or radioactivemicro spheres.

Without being limited by any theory, the compounds provided herein canrender abnormal cells more sensitive to treatment with radiation forpurposes of killing and/or inhibiting the growth of such cells.Accordingly, provided herein is a method for sensitizing abnormal cellsin a mammal to treatment with radiation which comprises administering tothe mammal an amount of a compound provided herein, or pharmaceuticallyacceptable salt, ester, prodrug, solvate, hydrate or derivative thereof,which amount is effective is sensitizing abnormal cells to treatmentwith radiation. The amount of the compound, salt, or solvate in thismethod can be determined according to the means for ascertainingeffective amounts of such compounds described herein.

In one embodiment, the compounds or pharmaceutical compositions providedherein can be used in combination with an amount of one or moresubstances selected from anti-angiogenesis agents, signal transductioninhibitors, antiproliferative agents, glycolysis inhibitors, orautophagy inhibitors.

In one embodiment, anti-angiogenesis agents, such as MMP-2(matrix-metalloprotienase 2) inhibitors, MMP-9 (matrix-metalloprotienase9) inhibitors, and COX-11 (cyclooxygenase 11) inhibitors, can be used inconjunction with a compound provided herein or a pharmaceuticalcomposition described herein. Examples of useful COX-II inhibitorsinclude Celebrex® (alecoxib), valdecoxib, and rofecoxib. Examples ofuseful matrix metalloproteinase inhibitors are described in, e.g., WO96/33172, WO 96/27583, European Patent Application No. 97304971.1,European Patent Application No. 99308617.2, WO 98/07697, WO 98/03516, WO98/34918, WO 98/34915, WO 98/33768, WO 98/30566, European PatentPublication 606,046, European Patent Publication 931,788, WO 90/05719,WO 99/52910, WO 99/52889, WO 99/29667, PCT International Application No.PCT/IB98/01113. European Patent Application No. 99302232.1, GreatBritain Patent Application No. 9912961.1, U.S. Pat. Nos. 7,030,242,5,863,949, 5,861,510, and European Patent Publication 780,386, all ofwhich are incorporated herein by reference in their entireties. In oneembodiment, MMP-2 and MMP-9 inhibitors are those that have little or noactivity inhibiting MMP-1, or are those that selectively inhibit MMP-2and/or MMP-9 relative to the other matrix-metalloproteinases (i.e.,MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12,and MMP-13). Some non-limiting examples of MMP inhibitors useful in thepresent disclosure are AG-3340, RO 32-3555, and RS 13-0830.

Autophagy inhibitors include, but are not limited to, chloroquine,3-methyladenine, hydroxychloroquine (Plaquenil™), bafilomycinA1,5-amino-4-imidazole carboxamide riboside (AICAR), okadaic acid,autophagy-suppressive algal toxins which inhibit protein phosphatases oftype 2A or type 1, analogues of cAMP, and drugs which elevate cAMPlevels such as adenosine, LY204002, N6-mercaptopurine riboside, andvinblastine. In addition, antisense or siRNA that inhibits expression ofproteins including, but not limited to ATG5 (which are implicated inautophagy), can also be used.

Also provided herein am a method of, and a pharmaceutical compositionfor, treating a cardiovascular disease in a mammal comprising an amountof a compound provided herein, or a pharmaceutically acceptable salt,ester, prodrug, solvate, hydrate or derivative thereof, and an amount ofone or more second therapeutic agent(s) useful for the treatment ofcardiovascular diseases.

Examples of second therapeutic agents for use in treating cardiovasculardiseases include, but are not limited to, anti-thrombotic agents, e.g.,prostacyclin and salicylates, thrombolytic agents, e.g., streptokinase,urokinase, tissue plasminogen activator (TPA) and anisoylatedplasminogen-streptokinase activator complex (APSAC), anti-plateletsagents, e.g., acetyl-salicylic acid (ASA) and clopidrogel, vasodilatingagents, e.g., nitrates, calcium channel blocking drugs,anti-proliferative agents, e.g., colchicine and alkylating agents,intercalating agents, growth modulating factors such as interleukins,transformation growth factor-beta and congeners of platelet derivedgrowth factor, monoclonal antibodies directed against growth factors,anti-inflammatory agents, both steroidal and non-steroidal, and otheragents that can modulate vessel tone, function, arteriosclerosis, andthe healing response to vessel or organ injury post intervention. In oneembodiment, a coating can be used to effect therapeutic delivery focallywithin the vessel wall. In one embodiment, antibiotics can also beincluded in combinations or coatings provided herein. In one embodiment,by incorporation of an active agent in a swellable polymer, the activeagent can be released upon swelling of the polymer.

In one embodiment, the compounds describe herein can be formulated oradministered in conjunction with liquid or solid tissue barriers alsoknown as lubricants. Examples of tissue barriers include, but are notlimited to, polysaccharides, polyglycans, seprafilm, interceed, andhyaluronic acid.

In one embodiment, medicaments that can be administered in conjunctionwith the compounds described herein include suitable drugs that can bedelivered by inhalation, for example, analgesics, e.g., codeine,dihydromorphine, ergotamine, fentanyl or morphine; anginal preparations,e.g., diltiazem; antiallergics, e.g., cromoglycate, ketotifen ornedocromil; anti-infectives, e.g., cephalosporins, penicillins,streptomycin, sulphonamides, tetracyclines or pentamidine;antihistamines, e.g., methapyrilene; anti-inflammatories, e.g.,beclomethasone, flunisolide, budesonide, tipredane, triamcinoloneacetonide or fluticasone; antitussives, e.g., noscapine;bronchodilators, e.g., ephedrine, adrenaline, fenoterol, formoterol,isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine,pirbuterol, reproterol, rimiterol, salbutamol, salmeterol, terbutalin,isoetharine, tulobuterol, orciprenaline or(−)-4-amino-3,5-dichloro-α-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]-amino]methyl]benzenemethanol;diuretics, e.g., amiloride; anticholinergics e.g., ipratropium, atropineor oxitropium; hormones, e.g., cortisone, hydrocortisone orprednisolone; xanthines e.g., aminophylline, choline theophyllinate,lysine theophyllinate or theophylline; and therapeutic proteins andpeptides, e.g., insulin or glucagon. In one embodiment, it will be clearto a person skilled in the art that, where appropriate, the medicamentscan be used in a form of salts (e.g., as alkali metal or amine salts oras acid addition salts) or as esters (e.g., lower alkyl esters) or assolvates (e.g., hydrates) to optimize the activity and/or stability ofthe medicament.

Other exemplary therapeutic agents useful for a combination therapyinclude, but are not limited to, agents as described herein, radiationtherapy, hormone antagonists, hormones and their releasing factors,thyroid and antithyroid drugs, estrogens and progestins, androgens,adrenocorticotropic hormone; adrenocortical steroids and their syntheticanalogs; inhibitors of the synthesis and actions of adrenocorticalhormones, insulin, oral hypoglycemic agents, and the pharmacology of theendocrine pancreas, agents affecting calcification and bone turnovercalcium, phosphate, parathyroid hormone, vitamin D, calcitonin, vitaminssuch as water-soluble vitamins, vitamin B complex, ascorbic acid,fat-soluble vitamins, vitamins A, K, and E, growth factors, cytokines,chemokines, muscarinic receptor agonists and antagonists;anticholinesterase agents; agents acting at the neuromuscular junctionand/or autonomic ganglia; catecholamines, sympathomimetic drugs, andadrenergic receptor agonists or antagonists; and 5-hydroxytryptamine(5-HT, serotonin) receptor agonists and antagonists.

In one embodiment, therapeutic agents can also include one or mom agentsfor pain and inflammation, such as, e.g., histamine and histamineantagonists, bradykinin and bradykinin antagonists, 5-hydroxytryptamine(serotonin), lipid substances that are generated by biotransformation ofthe products of the selective hydrolysis of membrane phospholipids,eicosanoids, prostaglandins, thromboxanes, leukotrienes, aspirin,nonsteroidal anti-inflammatory agents, analgesic-antipyretic agents,agents that inhibit the synthesis of prostaglandins and thromboxanes,selective inhibitors of the inducible cyclooxygenase, selectiveinhibitors of the inducible cyclooxygenase-2, autacoids, paracrinehormones, somatostatin, gastrin, cytokines that mediate interactionsinvolved in humoral and cellular immune responses, lipid-derivedautacoids, eicosanoids, β-adrenergic agonists, ipratropium,glucocorticoids, methylxanthines, sodium channel blockers, opioidreceptor agonists, calcium channel blockers, membrane stabilizers, andleukotriene inhibitors.

In one embodiment, additional therapeutic agents contemplated hereininclude diuretics, vasopressin, agents affecting the renal conservationof water, rennin, angiotensin, agents useful in the treatment ofmyocardial ischemia, anti-hypertensive agents, angiotensin convertingenzyme inhibitors, β-adrenergic receptor antagonists, agents for thetreatment of hypercholesterolemia, and agents for the treatment ofdyslipidemia.

In one embodiment, other therapeutic agents contemplated herein includedrugs used for control of gastric acidity, agents for the treatment ofpeptic ulcers, agents for the treatment of gastroesophageal refluxdisease, prokinetic agents, antiemetics, agents used in irritable bowelsyndrome, agents used for diarrhea, agents used for constipation, agentsused for inflammatory bowel disease, agents used for biliary disease,agents used for pancreatic disease, therapeutic agents used to treatprotozoan infections, drugs used to treat Malaria, Amebiasis,Giardiasis, Trichomoniasis, Trypanosomiasis, and/or Leishmaniasis,and/or drugs used in the chemotherapy of helminthiasis. In oneembodiment, other therapeutic agents include antimicrobial agents,sulfonamides, trimethoprim-sulfamethoxazole quinolones, and agents forurinary tract infections, penicillins, cephalosporins, and other,beta-Lactam antibiotics, an agent comprising an aminoglycoside, proteinsynthesis inhibitors, drugs used in the chemotherapy of tuberculosis,Mycobacterium avium complex disease, and leprosy, antifungal agents, andantiviral agents including nonretroviral agents and antiretroviralagents.

In one embodiment, examples of therapeutic antibodies that can becombined with a compound provided herein include, but are not limitedto, anti-receptor tyrosine kinase antibodies (cetuximab, panitumumab,trastuzumab), anti CD20 antibodies (rituximab, tositumomab), and otherantibodies such as alemtuzumab, bevacizumab, and gemtuzumab.

In other embodiments, therapeutic agents used for immunomodulation, suchas immunomodulators, immunosuppressive agents, tolerogens, andimmunostimulants, are contemplated by the methods provided herein. Infurther embodiments, therapeutic agents acting on the blood and theblood-forming organs, hematopoietic agents, growth factors, minerals,vitamins, anticoagulant, thrombolytic, and antiplatelet drugs arecontemplated by the methods provided herein.

In one embodiment, for treating renal carcinoma, one can combine acompound as disclosed herein, or a pharmaceutically acceptable form(e.g., pharmaceutically acceptable salts, hydrates, solvates, chelates,non-covalent complexes, isomers, prodrugs, and isotopically labeledderivatives) thereof, or pharmaceutical compositions as disclosedherein, with sorafenib and/or avastin. For treating an endometrialdisorder, one can combine a compound as disclosed herein withdoxorubincin, taxotere (taxol), and/or cisplatin (carboplatin). Fortreating ovarian cancer, one can combine a compound as disclosed hereinwith cisplatin (carboplatin), taxotere, doxorubincin, topotecan, and/ortamoxifen. For treating breast cancer, one can combine a compound asdisclosed herein with taxotere (Taxol®), gemcitabine (capecitabine),tamoxifen, letrozole, Taroeva®, lapatinib, PD0325901, Avastin®,Hereeptin®, OSI-906, and/or OSI-930. For treating lung cancer, one cancombine a compound as disclosed herein with taxotere (taxol),gemcitabine, cisplatin, pemetrexed, Tarceva®, PD0325901, and/orAvastin®.

In one embodiment, further therapeutic agents that can be combined witha subject compound can be found in Goodman and Gilman's “ThePharmacological Basis of Therapeutics” Eleventh Edition; or thePhysician's Desk Reference, both of which are incorporated herein byreference in their entirety.

In one embodiment, the compounds described herein can be used incombination with the agents disclosed herein or other suitable agents,depending on the condition being treated. Hence, in some embodiments thecompounds provided herein will be co-administered with other agents asdescribed herein. When used in combination therapy, the compoundsdescribed herein can be administered with the second agentsimultaneously or separately. This administration in combination caninclude simultaneous administration of the two agents in the same dosageform, simultaneous administration in separate dosage forms, and separateadministration. In one embodiment, a compound described herein and anyof the additional agents described herein can be formulated together inthe same dosage form and administered simultaneously. Alternatively, acompound provided herein and any of the additional agents describedherein can be simultaneously administered, wherein the compound and theagent(s) are present in separate formulations. In another alternative, acompound provided herein can be administered before, or after, theadministration of any of the additional agents described herein. In aseparate administration protocol, a compound provided herein and any ofthe additional agents described herein can be administered a few minutesapart, or a few hours apart, or a few days apart.

The examples and preparations provided below further illustrate andexemplify the compounds, polymorphs, and compositions provided hereinand methods of preparing such compounds, polymorphs, and compositions.It is to be understood that the scope of the present disclosure is notlimited in any way by the scope of the following examples andpreparations. In the following examples, molecules with a single chiralcenter, unless otherwise noted, exist as a racemic mixture. Thosemolecules with two or more chiral centers, unless otherwise noted, existas a racemic mixture of diastereomers. Single enantiomers/diastereomerscan be obtained by methods known to those skilled in the art.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.In case of conflict, the present application, including any definitionsherein, will control.

EXAMPLES Chemical Examples

Unless specified to the contrary, the reactions described herein takeplace at atmospheric pressure, generally within a temperature range from−10° C. to 200° C. Further, except as otherwise specified, reactiontimes and conditions are intended to be approximate, e.g., taking placeat about atmospheric pressure within a temperature range of about −10°C. to about 110° C. over a period that is, for example, about 1 to about24 hours, reactions left to run overnight in some embodiments canaverage a period of about 16 hours. As used herein, the term “volume” or“vol.” refers to 1 liter of solvent per kilogram of limiting reagent.

Isolation and purification of the chemical entities and intermediatesdescribed herein can be effected, optionally, by any suitable separationor purification procedure such as, for example, filtration, extraction,crystallization, column chromatography, thin-layer chromatography orthick-layer chromatography, or a combination of these procedures.Specific illustrations of suitable separation and isolation proceduresare given by reference to the examples hereinbelow. However, otherequivalent separation or isolation procedures can also be used.

In some embodiments, the (R)- and (S)-isomers of the non-limitingexemplary compounds, if present, can be resolved by methods known tothose skilled in the art, for example by formation of diastereoisomericsalts or complexes which can be separated, for example, bycrystallization; via formation of diastereoisomeric derivatives whichcan be separated, for example, by crystallization, gas-liquid or liquidchromatography; selective reaction of one enantiomer with anenantiomer-specific reagent, for example enzymatic oxidation orreduction, followed by separation of the modified and unmodifiedenantiomers; or gas-liquid or liquid chromatography in a chiralenvironment, for example on a chiral support, such as silica with abound chiral ligand or in the presence of a chiral solvent.Alternatively, a specific enantiomer can be synthesized by asymmetricsynthesis using optically active reagents, substrates, catalysts orsolvents, or by converting one enantiomer to the other by asymmetrictransformation.

The compounds described herein can be optionally contacted with apharmaceutically acceptable acid to form the corresponding acid additionsalts. Also, the compounds described herein can be optionally contactedwith a pharmaceutically acceptable base to form the corresponding basicaddition salts.

In some embodiments, disclosed compounds can generally be synthesized byan appropriate combination of generally well known synthetic methods.Techniques useful in synthesizing these chemical entities are bothreadily apparent and accessible to those of skill in the relevant art,based on the instant disclosure. Many of the optionally substitutedstarting compounds and other reactants are commercially available, e.g.,from Aldrich Chemical Company (Milwaukee, Wis.) or can be readilyprepared by those skilled in the art using commonly employed syntheticmethodology.

The discussion below is offered to illustrate certain of the diversemethods available for use in preparing the disclosed compounds and isnot intended to limit the scope of reactions or reaction sequences thatcan be used in preparing the compounds provided herein.

The polymorphs made according to the methods provided herein can becharacterized by any methodology known in the art. For example, thepolymorphs made according to the methods provided herein can becharacterized by X-ray powder diffraction (XRPD), differential scanningcalorimetry (DSC), thermogravimetric analysis (TGA), dynamic vaporsorption (DVS), hot-stage microscopy, optical microscopy, Karl Fischeranalysis, melting point, spectroscopy (e.g., Raman, solid state nuclearmagnetic resonance (ssNMR), liquid state nuclear magnetic resonance (¹H-and ¹³C-NMR), and FT-IR), thermal stability, grinding stability, andsolubility, among others.

XRPD

Compounds and polymorphs provided herein can be characterized by X-raypowder diffraction patterns (XRPD). The relative intensities of XRPDpeaks can vary depending upon the sample preparation technique, thesample mounting procedure and the particular instrument employed, amongother parameters. Moreover, instrument variation and other factors canaffect the 20 peak values. Therefore, in certain embodiments, the XRPDpeak assignments can vary by plus or minus about 0.2 degrees theta ormore, herein referred to as “(±0.2°)”.

XRPD patterns for each of Forms A-J and amorphous form of the compoundof Formula (I) were collected with a PANalytical CubiX XPert PRO MPDdiffractometer using an incident beam of CU radiation produced using anOptix long, fine-focus source. An elliptically graded multilayer mirrorwas used to focus Cu Kα X-rays through the specimen and onto thedetector. Samples were placed on Si zero-return ultra-micro sampleholders. Analysis was performed using a 10 mm irradiated width and thefollowing parameters were set within the hardware/software:

X-ray tub Cu Kα, 45 kV, 40 mA

Detector: X′Celerator

Slits: ASS Primary Slit: Fixed 1°

Divergence Slit (Prog): Automatic—5 mm irradiated length

Soller Slits: 0.02 radian

Scatter Slit (PASS): Automatic—5 mm observed length

Scanning

Scan Range: 3.0-45.0°

Scan Mode: Continuous

Step Size: 0.03°

Time per Step: 10 s

Active Length: 2.54°

DSC

Compounds and polymorphs provided herein can be characterized by acharacteristic differential scanning calorimeter (DSC) thermogram. ForDSC, it is known in the art that the peak temperatures observed willdepend upon the rate of temperature change, the sample preparationtechnique, and the particular instrument employed, among otherparameters. Thus, the peak values in the DSC thermograms reported hereincan vary by plus or minus about 2° C., plus or minus about 3° C., plusor minus about 4° C., plus or minus about 5° C., plus or minus about 6°C., to plus or minus about 7° C., or more. For some polymorph Forms, DSCanalysis was performed on more than one sample which illustrates theknown variability in peak position, for example, due to the factorsmentioned above. The observed peak positional differences are in keepingwith expectation by those skilled in the art as indicative of differentsamples of a single polymorph Form of a compound of Formula (I).

Impurities in a sample can also affect the peaks observed in any givenDSC thermogram. In some embodiments, one or more chemical entities thatare not the polymorph of a compound of Formula (I) in a sample beinganalyzed by DSC can result in one or more peaks at lower temperaturethan peak(s) associated with the transition temperature of a givenpolymorph as disclosed herein.

DSC analyses were performed using a Mettler 822e differential scanningcalorimeter. Samples were weighed in an aluminum pan, covered with apierced lid, and then crimped. General analysis conditions were about30° C. to about 300° C.-about 350° C. ramped at about 10° C./min.Several additional ramp rates were utilized as part of the investigationinto the high melt Form B, including about 2° C./min, about 5° C./min,and about 20° C./min. Samples were analyzed at multiple ramp rates tomeasure thermal and kinetic transitions observed.

Isothermal holding experiments were also performed utilizing the DSC.Samples were ramped at about 10° C./min to temperature (about 100° C. toabout 250° C.) and held for about five minutes at temperature beforerapid cooling to room temperature. In these cases, samples were thenanalyzed by XRPD or reanalyzed by DSC analysis.

TGA

A polymorphic form provided herein can give rise to thermal behaviordifferent from that of an amorphous material or another polymorphicform. Thermal behavior can be measured in the laboratory bythermogravimetric analysis (TGA) which can be used to distinguish somepolymorphic forms from others. In one embodiment, a polymorph asdisclosed herein can be characterized by thermogravimetric analysis.

TGA analyses were performed using a Mettler 851c SDTA/TGA thermalgravimetric analyzer. Samples were weighed in an alumina crucible andanalyzed from about 30° C. to about 230° C. and at a ramp rate of about10° C./min.

DVS

Compounds and polymorphs provided herein can be characterized bymoisture sorption analysis. This analysis was performed using a HidenIGAsorp Moisture Sorption instrument. Moisture sorption experiments werecarried out at about 25° C. by performing an adsorption scan from about40% to about 90% RH in steps of about 10% RH and a desorption scan fromabout 85% to about 0% RH in steps of about −10% RH. A second adsorptionscan from about 10% to about 40% RH was performed to determine themoisture uptake from a drying state to the starting humidity. Sampleswere allowed to equilibrate for about four hours at each point or untilan asymptotic weight was reached. After the isothermal sorption scan,samples were dried for about one hour at elevated temperature (about 60°C.) to obtain the dry weight. XRPD analysis on the material followingmoisture sorption was performed to determine the solid form.

Optical Microscopy

Compounds and polymorphs provided herein can be characterized bymicroscopy, such as optical microscopy. Optical microscopy analysis wasperformed using a Leica DMRB Polarized Microscope. Samples were examinedwith a polarized light microscope combined with a digital camera(1600×1200 resolution). Small amounts of samples were dispersed inmineral oil on a glass slide with cover slips and viewed with 100×magnification.

Karl Fischer Analysis

Compounds and polymorphs provided herein can be characterized by KarlFischer analysis to determine water content. Karl Fischer analysis wasperformed using a Metrohm 756 KF Coulometer. Karl Fisher titration wasperformed by adding sufficient material to obtain 50 μg of water, about10 to about 50 mg of sample, to AD coulomat.

Raman Spectroscopy

Compounds and polymorphs provided herein can be characterized by Ramanspectroscopy. Raman spectroscopy analysis was performed using a KaiserRamanRXN1 instrument with the samples in a glass well. Raman spectrawere collected using a PhAT macroscope at about 785 nm irradiationfrequency and about 1.2 mm spot size. Samples were analyzed using 12 to16 accumulations with about 0.5 to about 12 second exposure time andutilized cosmic ray filtering. The data was processed by backgroundsubtraction of an empty well collected with the same conditions. Abaseline correction and smoothing was performed to obtain interpretabledata when necessary.

FT-IR

Compounds and polymorphs provided herein can be characterized by FT-IRspectroscopy. FT-IR spectroscopy was performed using either a NicoletNexus 470 or Avatar 370 Infrared Spectrometer and the OMNIC software.Samples were analyzed using a diamond Attenuated Total Reflection (ATR)accessory. A compound sample was applied to the diamond crystal surfaceand the ATR knob was turned to apply the appropriate pressure. Thespectrum was then acquired and analyzed using the OMNIC software.Alternative sample preparations include solution cells, mulls, thinfilms, and pressed discs, such as those made of KBr, as known in theart.

NMR

Compounds and polymorphs provided herein can be characterized by nuclearmagnetic resonance (NMR). NMR spectra were obtained using a 500 MHzBruker AVANCE with 5-mm BBO probe instrument. Samples (approximately 2to approximately 10 mg) were dissolved in DMSO-d6 with 0.05%tetramethylsilane (TMS) for internal reference. ¹H-NMR spectra wereacquired at 500 MHz using 5 mm broadband observe (1H-X) Z gradientprobe. A 30 degree pulse with 20 ppm spectral width, 1.0 s repetitionrate, and 32-64 transients were utilized in acquiring the spectra.

High-Performance Liquid Chromatography

Compounds and polymorphs provided herein can be analyzed byhigh-performance liquid chromatography using an Agilent 1100 instrument.The instrument parameters for achiral HPLC are as follows:

Column: Sunfire C 1 8 4.6×150 mm Column Temperature: AmbientAuto-sampler Temperature: Ambient Detection: UV at 250 nm

Mobile Phase A: 0.05% trifluoroacetic acid in waterMobile Phase B: 0.05% trifluoroacetic acid in McCNFlow Rate: 1. mL/minute

Injection Volume: 10 μL

Data Collection time: 20 minutesRe-equilibration Time: 5 minutes

Diluent & Needle Wash: MeOH Gradient Conditions:

Time (minutes) % A % B 0.0 90 10 3.5 90 10 10.0 10 90 15.0 10 90 18.0 9010 20.0 90 10

Compounds and polymorphs provided herein can be analyzed byhigh-performance liquid chromatography using a chiral HPLC column todetermine % cc values:

Column: Chiralpak IC, 4.6 mm×250 mm, 5 μm.

Column Temperature: Room Temperature Sample Temperature: RoomTemperature Detection: UV at 254 nm

Mobile Phase A: 60% Hexane 40% (IPA:EtOH=2:3) with 0.2% Acetic Acid and0.1% DEA

Isocratic: 100% A

Flow Rate: 1 mL/min

Diluent: Methanol Injection Volume: 10 μL Analysis Time: 25 min Example1 Synthesis of(S)-3-(1-aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one Example 1A

Compound 1 (6.00 kg) was treated with 1-hydroxybenzotriazole monohydrate(HOBt.H₂O), triethylamine, N,O-dimethylhydroxylamine hydrochloride, andEDCI in dimethyllactamide (DMA) at 10° C. The reaction was monitored byproton NMR and deemed complete after 2.6 hours, affording Compound 2 asa white solid in 95% yield. The R-enantiomer was not detected by protonNMR using (R)-(−)-alpha-acetylmandelic acid as a chiral-shift reagent.

Example 1B

Compound 3 (4.60 kg) was treated with p-toluenesulfonic acid monohydrateand 3,4-dihydro-2H-pyran (DHP) in ethyl acetate at 75° C. for 2.6 hours.The reaction was monitored by HPLC. Upon completion of the reaction,Compound 4 was obtained as a yellow solid in 80% yield with >99% (AUC)purity by HPLC analysis.

Example 1C

Compound 5 (3.30 kg) was treated with thionyl chloride and a catalyticamount of DMF in methylene chloride at 25° C. for five hours. Thereaction was monitored by HPLC which indicated a 97.5% (AUC) conversionto compound 6. Compound 6 was treated in situ with aniline in methylenechloride at 25° C. for 15 hours. The reaction was monitored by HPLC andafforded Compound 7 as a brown solid in 81% yield with >99% (AUC) purityby HPLC analysis.

Compound 2 was treated with 2.0 M isopropyl Grignard in THF at −20° C.The resulting solution was added to Compound 7 (3.30 kg) pre-treatedwith 2.3 M n-hexyl lithium in tetrahydrofuran at −15° C. The reactionwas monitored by HPLC until a 99/9 (AUC) conversion to Compound 8 wasobserved. Compound 8 was treated in situ with concentrated HCl inisopropyl alcohol at 70° C. for eight hours. The reaction was monitoredby HPLC and afforded Compound 9 as a brown solid in 85% yield with 98%(AUC) purity and 84% (AUC) cc by HPLC analysis.

Example 1D

Compound 9 (3.40 kg) was treated with D-tartaric acid in methanol at 55°C. for 1-2 hours. The batch was filtered and treated with ammoniumhydroxide in deionized (DI) water to afford enantiomerically enrichedCompound 9 as a tan solid in 71% yield with >99% (AUC) purity and 91%(AUC) cc by HPLC analysis.

Example 2 Synthesis of(S)-3-(1-aminoethyl)-8-chlor-2-phenylisoquinolin-1(2H)-one

Example 2A

To Compound 7 (20.1 g) was charged 100 mL of anhydrous THF. Theresulting solution was cooled to about −10° C. and 80 mL of n-hexyllithium (2.3 M in hexanes, 2.26 equiv.) was slowly added (e.g., overabout 20 min). The resulting solution was stirred at about −10° C. forabout 20 min.

To Compound 2 (26.5 g; 1.39 equiv.) was charged 120 mL of anhydrous THF.The resulting mixture was cooled to about −10° C. and 60 mL of isopropylmagnesium chloride (2.0 M in THF, 1.47 equiv.) was slowly added (e.g.,over about 15-20 min). The resulting mixture was then stirred at about−10° C. for about 20 min. The mixture prepared from Compound 2 was addedto the solution prepared from Compound 7 while maintaining the internaltemperature between about −10 and about 0° C. After the addition wascomplete (about 5 min), the cold bath was removed, and the resultingmixture was stirred at ambient temperature for about 1 h, then cooled.

A solution of 100 mL of anisole and 33 mL of isobutyric acid (4.37equiv.) was prepared. The anisole solution was cooled to an internaltemperature of about −3° C. The above reaction mixture was added to theanisole solution such that the internal temperature of the anisolesolution was maintained at below about 5° C. The ice bath was thenremoved (after about 15 min, the internal temperature was about 7° C.).To the mixture, 100 mL of 10 wt % aqueous NaCl solution was rapidlyadded (the internal temperature increased from about 7° C. to about 15°C.). After stirring for about 30 min, the two phases were separated. Theorganic phase was washed with another 100 mL of 10 wt % aqueous NaCl.The organic phase was transferred to a flask using 25 mL of anisole tofacilitate the transfer. The anisole solution was then concentrated to109 g. Then, 100 mL of anisole was added.

To the approximately 200 mL of anisole solution was added 50 mL of TFA(8 equiv.) while maintaining the internal temperature below about 45-50°C. The resulting solution warmed to about 45-50° C. and stirred forabout 15 hrs, then cooled to 20-25° C. To this solution was added 300 mLof MTBE dropwise and then the resulting mixture was held at 20-25° C.for 1 h. The mixture was filtered, and the wet cake washed withapproximately 50 mL of MTBE. The wet cake was conditioned on the filterfor about 1 h under nitrogen. The wet cake was periodically mixed andre-smoothed during conditioning. The wet cake was then washed with 200mL of MTBE. The wet cake was further conditioned for about 2 h (the wetcake was mixed and resmoothed after about 1.5 h). The wet cake was driedin a vacuum oven at about 40° C. for about 18 h to afford Compound 9-TFAsalt in about 97.3% purity (AUC), which had about 99.1% S-enantiomer(e.g., chiral purity of about 99.1%).

Compound 9-TFA salt (3 g) was suspended in 30 mL of EtOAc at about 20°C. To the EtOAc suspension was added 4.5 mL (2.2 eq.) of a 14% aqueousammonium hydroxide solution and the internal temperature decreased toabout 17° C. Water (5 mL) was added to the biphasic mixture. Thebiphasic mixture was stirred for 30 min. The mixing was stopped and thephases were allowed to separate. The aqueous phase was removed. To theorganic phase (combined with 5 mL of EtOAc) was added 10 mL of 10%aqueous NaCl. The biphasic mixture was stirred for about 30 min. Theaqueous phase was removed. The organic layer was concentrated to 9 g. Tothis EtOAc mixture was added 20 mL of i-PrOAc. The resulting mixture wasconcentrated to 14.8 g. With stirring, 10 mL of n-heptane was addeddropwise. The suspension was stirred for about 30 min, then anadditional 10 mL of n-heptane was added. The resulting suspension wasstirred for 1 h. The suspension was filtered and the wet cake was washedwith additional heptane. The wet cake was conditioned for 20 min undernitrogen, then dried in a vacuum oven at about 40° C. to afford Compound9 free base in about 99.3% purity (AUC), which had about 99.2%S-enantiomer (e.g., chiral purity of about 99.2%).

Example 2B

A mixture of Compound 7 (100 g, 0.407 mol, 1 wt) and THF (500 mL, 5 vol)was prepared and cooled to about 3° C. n-Hexyllithium (2.3 M in hexanes,400 mL, 0.920 mol, 2.26 equiv) was charged over about 110 minutes whilemaintaining the temperature below about 6° C. The resulting solution wasstirred at 0±5° C. for about 30 minutes. Concurrently, a mixture ofCompound 2 (126 g, 0.541 mol, 1.33 cquiv) and THF (575 mL, 5.8 vol) wasprepared. The resulting slurry was charged with isopropylmagnesiumchloride (2.0 M in THF, 290 mL, 0.574 mol, 1.41 equiv) over about 85minutes while maintaining the temperature below about 5° C. Theresulting mixture was stirred for about 35 minutes at 0±5° C. TheCompound 2 magnesium salt mixture was transferred to the Compound 7lithium salt mixture over about 1 hour while maintaining a temperatureof 0±5° C. The solution was stirred for about 6 minutes upon completionof the transfer.

The solution was added to an about −5° C. stirring solution ofisobutyric acid (165 mL, 1.78 mol, 4.37 equiv) in anisole (500 mL, 5vol) over about 20 minutes during which time the temperature did notexceed about 6° C. The resulting solution was stirred for about 40minutes while being warmed to about 14° C. Then, a 10% sodium chloridesolution (500 mL, 5 vol) was rapidly added to the reaction. Thetemperature rose to about 21° C. After agitating the mixture for about 6minutes, the stirring was ceased and the lower aqueous layer was removed(about 700 mL). A second portion of 10% sodium chloride solution (500mL, 5 vol) was added and the mixture was stirred for 5 minutes. Then,the stirring was ceased and the lower aqueous layer was removed. Thevolume of the organic layer was reduced by vacuum distillation to about750 mL (7.5 vol).

Trifluoroacetic acid (250 mL, 3.26 mol, 8.0 equiv) was added and theresulting mixture was agitated at about 45° C. for about 15 hours. Themixture was cooled to about 35° C. and MTBE (1.5 L, 15 vol) was addedover about 70 minutes. Upon completion of the addition, the mixture wasagitated for about 45 minutes at about 25-30° C. The solids werecollected by vacuum filtration and conditioned under N₂ for about 20hours to afford Compound 9-TFA salt in about 97.5% purity (AUC), whichhad a chiral purity of about 99.3%.

Compound 9⋅TFA salt (100 g) was suspended EtOAc (1 L, 10 vol) and 14%aqueous ammonia (250 mL, 2.5 vol). The mixture was agitated for about 30minutes, then the lower aqueous layer was removed. A second portion of14% aqueous ammonia (250 mL, 2.5 vol) was added to the organic layer.The mixture was stirred for 30 minutes, then the lower aqueous layer wasremoved. Isopropyl acetate (300 mL, 3 vol) was added, and the mixturewas distilled under vacuum to 500 mL (5 vol) while periodically addingin additional isopropyl acetate (1 L, 10 vol).

Then, after vacuum-distilling to a volume of 600 mL (6 vol), heptanes(1.5 L, 15 vol) were added over about 110 minutes while maintaining atemperature between about 20° C. and about 30° C. The resulting slurrywas stirred for about 1 hour, then the solid was collected by vacuumfiltration. The cake was washed with heptanes (330 mL, 3.3 vol) andconditioned for about 1 hour. The solid was dried in an about 45° C.vacuum oven for about 20 hours to afford Compound 9 free base in about99.23% purity (AUC), which has a chiral purity of about 99.4%.

Example 3 Chiral Resolution of(S)-3-(1-aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (Compound 9)

In some instances,(S)-3-(l-aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (Compound 9)obtained by synthesis contained a minor amount of the corresponding(R)-isomer. Chiral resolution procedures were utilized to improve theenantiomeric purity of certain samples of(S)-3-(I-aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one.

In one experiment. Compound 9 (3.40 kg) was treated with D-tartaric acidin methanol at about 55° C. for about 1 to about 2 hours. The mixturewas filtered and treated with ammonium hydroxide in deionized (DI) waterto afford Compound 9 in greater than about 99% (AUC) purity, which had achiral purity of about 91% (AUC).

In another procedure, MeOH (10 vol.) and Compound 9 (1 equiv.) werestirred at 55±5° C. D-Tartaric acid (0.95 equiv.) was charged. Themixture was held at 55 t 5° C. for about 30 min and then cooled to about20 to about 25° C. over about 3 h. The mixture was held for about 30 minand then filtered. The filter cake was washed with MeOH (2.5 vol.) andthen conditioned. The cake was returned to the reactor and water (16vol.) was charged. The mixture was stirred at 25±5° C. NH₄OH was thencharged over about 1 h adjusting the pH to about 8 to about 9. Themixture was then filtered and the cake was washed with water (4 vol.)and then heptanes (4 vol.). The cake was conditioned and then vacuumdried at 45-50° C. to afford Compound 9 free base with a chiral purityof about 99.0%.

Example 4 Synthesis of(S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one

A mixture of Compound 7 (1 equiv.) and anhydrous THF (5 vol.) wasprepared. Separately, a mixture of Compound 2 (1.3 cquiv.) and anhydrousTHF (5 vol.) was prepared. Both mixtures were stirred for about 15 minat about 20 to about 25° C. and then cooled to −25±15° C. n-Hexyllithium (2.05 equiv.) was added to the Compound 7 mixture, maintainingthe temperature at >5° C. i-PrMgCl (1.33 equiv.) was added to theCompound 2 mixture, maintaining the temperature at >5° C. The Compound 2mixture was transferred to the Compound 7 mixture under anhydrousconditions at 0±5° C. The resulting mixture was warmed to 20±2° C. andheld for about 1 h. Then, the reaction was cooled to −5±5° C., and 6 NHCl (3.5 equiv.) was added to quench the reaction, maintainingtemperature at below about 25° C. The aqueous layer was drained, and theorganic layer was distilled under reduced pressure until the volume was2-3 volumes. IPA (3 vol.) was added and vacuum distillation wascontinued until the volume was 2-3 volumes. IPA (8 vol.) was added andthe mixture temperature was adjusted to about 60° C. to about 75° C.Cone. HCl (1.5 vol.) was added and the mixture was subsequently held for4 hours. The mixture was distilled under reduced pressure until thevolume was 2.5-3.5 volumes. The mixture temperature was adjusted to30±10° C. DI water (3 vol.) and DCM (7 vol.) were respectively added tothe mixture. Then, NH₄OH was added to the mixture, adjusting the pH toabout 7.5 to about 9. The temperature was adjusted to about 20 to about25° C. The layers were separated and the aqueous layer was washed withDCM (0.3 vol.). The combined DCM layers were distilled until the volumewas 2 volumes. i-PrOAc (3 vol.) was added and vacuum distillation wascontinued until the volume was 3 volumes. The temperature was adjustedto about 15 to about 30° C. Heptane (12 vol.) was charged to the organiclayer, and the mixture was held for 30 min. The mixture was filtered andfilter cake was washed with heptane (3 vol.). The cake was vacuum driedat about 45° C. afford Compound 9.

Then, MeOH (10 vol.) and Compound 9 (1 equiv.) were combined and stirredwhile the temperature was adjusted to 55±5° C. D-Tartaric acid (0.95equiv.) was charged. The mixture was held at 55±5° C. for about 30 minand then cooled to about 20 to about 25° C. over about 3 h. The mixturewas held for 30 min and then filtered. The filter cake was washed withMeOH (2.5 vol.) and then conditioned. Water (16 vol.) was added to thecake and the mixture was stirred at 25±5° C. NH₄OH was charged over 1 hadjusting the pH to about 8 to about 9. The mixture was then filteredand the resulting cake washed with water (4 vol.) and then heptanes (4vol.). The cake was conditioned and then vacuum dried at 45-50° C. toafford Compound 9.

To a mixture of i-PrOH (4 vol.) and Compound 9 (1 equiv.) was addedCompound 4 (1.8 equiv.), Et₃N (2.5 equiv.) and i-PrOH (4 vol.). Themixture was agitated and the temperature was adjusted to 82±5° C. Themixture was held for 24 h. Then the mixture was cooled to about 20 toabout 25° C. over about 2 h. The mixture was filtered and the cake waswashed with i-PrOH (2 vol.), DI water (25 vol.) and n-heptane (2 vol.)respectively. The cake was conditioned and then vacuum dried at 50±5° C.to afford Compound 10. To a mixture of EtOH (2.5 vol.) and Compound 10(1 equiv.) was added EtOH (2.5 vol.) and DI water (2 vol.). The mixturewas agitated at about 20 to about 25° C. Cone. HCl (3.5 equiv.) wasadded and the temperature was adjusted to 35±5° C. The mixture was heldfor about 1.5 h. The mixture was cooled to 25 t 5° C. and then polishfiltered to a particulate free vessel. NH₄OH was added, adjusting the pHto about 8 to about 9. Crystal seeds of Form C of a compound of Formula(I) (0.3 wt %) were added to the mixture which was held for 30 minutes.DI water (13 vol.) was added over about 2 h. The mixture was held for 1h and then filtered. The resulting cake was washed with DI water (4vol.) and n-heptane (2 vol.) respectively. The cake was conditioned forabout 24 h and then DCM (5 vol.) was added. This mixture was agitatedfor about 12 h at about 20 to about 25° C. The mixture was filtered andthe cake washed with DCM (1 vol.). The cake was conditioned for about 6h. The cake was then vacuum-dried at 50±5° C. To the cake was added DIwater (10 vol.), and i-PrOH (0.8 vol.) and the mixture was agitated at25±5° C. for about 6 h. An XRPD sample confirmed the compound of Formula(I) was Form C. The mixture was filtered and the cake was washed with DIwater (5 vol.) followed by n-heptane (3 vol.). The cake was conditionedand then vacuum dried at 50±5° C. to afford a compound of Formula (I) aspolymorph Form C.

Example 5 Synthesis of(S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one

Example 5A

Compound 9 (2.39 kg) was treated with Compound 4 and triethylamine inisopropyl alcohol at 80° C. for 24 hours. The reaction was monitored byHPLC until completion, affording8-chloro-2-phenyl-3-((1S)-1-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-ylamino)ethyl)isoquinolin-1(2H)-one(compound 10) as a tan solid in 94% yield with 98% (AUC) purity by HPLCanalysis.

8-Chloro-2-phenyl-3-((1S)-1-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-ylamino)ethyl)-isoquinolin-1(2H)-one(compound 10) (3.63 kg) was treated with HCl in ethanol at 30° C. for2.3 hours. The reaction was monitored by HPLC until completion, andafforded a compound of Formula (I) as a tan solid in 92% yield with >99%(AUC) purity and 90.9% (AUC) cc by HPLC analysis.

Example 5B 3-(1-Aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one(Compound 9)(0.72 mmol), 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine(Compound 4) (344 mg, 1.44 mmol) and DIPEA

(279 mg, 2.16 mmol) were dissolved in n-BuOH (20 mL), and the resultingmixture was stirred at reflux for 16 h. The reaction mixture wasconcentrated in vacuo and purified by flash column chromatography onsilica gel (cluting with 30% to 50% Hex/EA) to afford the product,8-chloro-2-phenyl-3-((1S)-1-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-ylamino)ethyl)isoquinolin-1(2H)-one(Compound 10), as a white solid (60% yield).

8-Chloro-2-phenyl-3-((1S)-1-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-ylamino)ethyl)-isoquinolin-1(2H)-one(Compound 10) (0.42 mmol) was dissolved in HCl/EtOH (3 M, 5 mL), and theresulting mixture was stirred at room temperature for 1 h. The reactionmixture was quenched with saturated NaHCO₃ aqueous solution and the pHwas adjusted to about 7-8. The mixture was extracted with CH₂Cl₂ (50mL×3), dried over anhydrous Na₂SO₄, and filtered. The filtrate wasconcentrated in vacuo, and the residue was recrystallized from ethylacetate and hexanes (1:1). The solid was collected by filtration anddried in vacuo to afford the product(S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one(Formula (I)) (90% yield) as a white solid as polymorph Form A.

Example 5C

3-(1-Aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (Compound 9) and6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (Compound 4) arecombined in the presence of triethylamine and isopropyl alcohol. Thereaction solution is heated at 82° C. for 24 hours to afford Compound10. The intermediate compound 10 is treated with concentrated HCl andethanol under aqueous conditions at 35° C. to remove thetetrahydropyranyl group to yield(S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one.Isolation/purification under aqueous conditions affords polymorph FormC.

Example 6 Synthesis of(S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one

3-(1-Aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (Compound 9)(150 g; 90% ee) and 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine(Compound 4) (216 g, 1.8 equiv) were charged to a round bottom flaskfollowed by addition of IPA (1.2 L; 8 vol) and triethylamine (175 mL;2.5 equiv). The resultant slurry was stirred at reflux for one day.Heptane (1.5 L; 10 vol) was added dropwise over two hours. The batch wasthen cooled to 0-5° C., held for one hour and filtered. The cake waswashed with heptane (450 mL; 3 vol) and returned to the reactor. IPA(300 mL; 2 vol) and water (2.25 L; 15 vol) were added and the resultantslurry stirred at 20-25° C. for three and half hours then filtered. Thecake was washed with water (1.5 L; 10 vol) and heptane (450 mL; 3 vol)and then vacuum dried at 48° C. for two and half days to give 227 g(90.1%) of the intermediate (Compound 10) as an off-white solidwith >99% (AUC) purity and >94% ee (chiral HPLC). The ee was determinedby converting a sample of the cake to the final product and analyzing itwith chiral HPLC.

The intermediate (Compound 10) (200 g) was slurried in an ethanol (900mL; 4.5 vol)/water (300 mL; 1.5 vol) mixture at 22° C. followed byaddition of conc. HCl (300 mL; 1.5 vol) and holding for one and halfhours at 25-35° C. Addition of HCl resulted in complete dissolution ofall solids producing a dark brown solution. Ammonium hydroxide (260 mL)was added adjusting the pH to 8-9. Product seeds of polymorph Form C(0.5 g) (Form A seeds can also be used) were then added and the batchwhich was held for ten minutes followed by addition of water (3 L; 15vol) over two hours resulting in crystallization of the product. Thebatch was held for 3.5 hours at 20-25° C. and then filtered. The cakewas washed with water (1 L; 5 vol) followed by heptane (800 mL; 4 vol)and vacuum dried at 52° C. for 23 hours to give 155.5 g (93.5%) ofproduct with 99.6% (AUC) purity and 93.8% ee (chiral HPLC).

Example 7 Synthesis of(S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one

A mixture of isopropanol (20.20 kg, 8 vol.), Compound 9 (3.17 kg, 9.04mol, 1 eq.), Compound 4 (4.61 kg, 16.27 mol, 1.8 eq.) and triethylamine(2.62 kg, 20.02 mol, 2.4 eq.) was prepared and heated to an internaltemperature of 82±5° C. The mixture was stirred at that temperature foran additional about 24 h. The temperature was adjusted to 20±5° C.slowly over a period of about 2 h and the solids were isolated viavacuum filtration through a 24″ polypropylene table top filter equippedwith a Sharkskin paper. The filter cake was rinsed sequentially with IPA(5.15 kg, 3 vol.), purified water (80.80 kg, 25 vol.) and n-heptane(4.30 kg, 2 vol.). The cake was further dried for about 4 days in vacuoat 50±5° C. to afford Compound 10.

To a mixture of ethanol (17.7 kg, 5 vol.) and Compound 10 (4.45 kg, 8.88mol. 1.0 eq.) was added purified water (8.94 kg, 2 vol.). To thismixture was slowly added concentrated HCl (3.10 kg, 3.5 eq.) whilemaintaining the temperature below about 35° C. The mixture was stirredat 30±5° C. for about 1.5 h and HPLC analysis indicated the presence thecompound of Formula (I) in 99.8% (AUC) purity with respect to compound10.

Then, the compound of Formula (I) mixture was cooled to 25±5° C. The pHof the mixture was adjusted to about 8 using pre filtered ammoniumhydroxide (1.90 kg). After stirring for about 15 min, Form C crystalseeds (13.88 g) were added. After stirring for about 15 min, purifiedwater (58.0 kg, 13 vol.) was charged over a period of about 2 h. Afterstirring the mixture for 15 h at 25±5° C., the solids were isolated viavacuum filtration through a 24″ polypropylene table top filter equippedwith a PTFE cloth over Sharkskin paper. The filter cake was rinsed withpurified water (18.55 kg, 4 vol.) followed by pre-filtered n-heptane(6.10 kg, 2 vol.). After conditioning the filter cake for about 24 h,HPLC analysis of the filter cake indicated the presence the compound ofFormula (I) in about 99.2% (AUC) purity.

To the filter cake was added dichloromethane (29.9 kg, 5 vol.) and theslurry was stirred at 25±5° C. for about 24 h. The solids were isolatedvia vacuum filtration through a 24″ polypropylene table top filterequipped with a PTFE cloth over Sharkskin paper, and the filter cake wasrinsed with DCM (6.10 kg, 1 vol.). After conditioning the filter cakefor about 22 h, the filter cake was dried for about 2 days in vacuo at50 t 5° C. to afford the compound of Formula (I) in 99.6% (AUC) purity.The compound of Formula (I) was consistent with a Form A reference byXRPD.

To this solid was added purified water (44.6 kg, 10 vol.) and prefiltered 2-propanol (3.0 kg, 0.8 vol.). After stirring for about 6 h, asample of the solids in the slurry was analyzed by XRPD and wasconsistent with a Form C reference. The solids were isolated via vacuumfiltration through a 24″ polypropylene table top filter equipped with aPTFE cloth over Sharkskin paper, and the filter cake was rinsed withpurified water (22.35 kg, 5 vol.) followed by pre filtered n-heptane(9.15 kg, 3 vol.). After conditioning the filter cake for about 18 h,the filter cake was dried in vacuo for about 5 days at 50±5° C.

This process afforded a compound of Formula (I) in about 99.6% (AUC)purity, and a chiral purity of greater than about 99/6 (AUC). An XRPD ofthe solid was consistent with a Form C reference standard. ¹H NMR(DMSO-d₆) and IR of the product conformed with reference standard.

Example 8 Analytical Data of(S)-3-(1-(9H-purin-6-ylamino)ethyl)-chloro-2-phenylisoquinolin-1(2H)-one

Provided herein are analytical data of various purified samples of(S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one,the compound of Formula (I). Confirmation of the structure of thecompound of Formula (I) was obtained via single crystal X-raydiffraction, FT-IR, ¹H-NMR and ¹³C-NMR spectra.

A single crystal structure of a tert-butyl methyl ether solvate of(S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one(e.g., polymorph Form G) was generated and single crystal X-ray data wascollected. The structure is shown in FIG. 26 , which further confirmedthe absolute stereochemistry as the S-enantiomer.

FT-IR spectra of Form C of(S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-onewas obtained, and shown in FIG. 27 .

¹H-NMR and ¹³C-NMR spectra of a sample of Form C of(S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-onewere obtained, and are provided in FIG. 28 and FIG. 29 , respectively.

Example 9 General Methods for the Preparation of Polymorphs Form A, B,C, D, E, F, G, H, I, J of the Compound of Formula (I)

General Method A: Single Solvent Crystallization with Fast Cooling orSlow Cooling

A sample of a compound of Formula (I)(e.g., Form A or Form C) is placedinto a vial equipped with stir bar and dissolved with a minimal amountof solvent (such as about 0.2 mL to about 0.3 mL) at an elevatedtemperature. The resulting solution is polish filtered through a 0.45 μmsyringe filter into a clean preheated vial. After hot filtration, thevial is placed in a refrigerator (e.g., about 4° C.) overnight in a fastcooling procedure, or cooled to ambient temperature at a rate of about20° C./h and allowed to equilibrate without stirring at ambienttemperature overnight in a slow cooling procedure. Optionally, a samplewithout solids can be scratched with an implement known in the art(e.g., a spatula) to initiate crystallization. The solution can beallowed to equilibrate for a period of time, such as approximately 8hours. For a slow cooling sample, if scratching does not provide solidsafter about 8 hours, then a stir bar can be added and the sample thenstirred overnight. A sample without precipitation can be evaporated todryness under a gentle gas stream, such as argon, nitrogen, ambient air,etc. The precipitated solids can be recovered by vacuum filtration,centrifuge filtration, or decanted as appropriate to afford the Form asindicated below.

General Method B: Multi-Solvent Crystallization with Fast Cooling orSlow Cooling

Multi-solvent (e.g., binary) solvent crystallizations can be performed.Primary solvents include, but are not limited to, ethanol, isopropylalcohol, methanol, tetrahydrofuran, acetone, methyl ethyl ketone,dioxane, NMP, DME, and DMF. Anti-solvents include, but are not limitedto, MTBE, DCM, toluene, heptane, and water.

A sample of a compound of Formula (I) (e.g., Form A or Form C) is placedinto a vial equipped with stir bar and dissolved with a minimal amountof solvent (such as about 0.2 mL to about 0.3 mL) at an elevatedtemperature. The resulting solution is polish filtered through a 0.45 μmsyringe filter into a clean preheated vial. After hot filtration, theanti-solvent is added until turbidity is observed. After hot filtration,the vial is placed in a refrigerator (e.g., about 4° C.) overnight in afast cooling procedure, or cooled to ambient temperature at a rate ofabout 20° C./h and allowed to equilibrate without stirring at ambienttemperature overnight in a slow cooling procedure. Optionally, a samplewithout solids can be scratched with an implement known in the art(e.g., a spatula) to initiate crystallization. The solution can beallowed to equilibrate for a period of time, such as approximately 8hours. For a slow cooling sample, if scratching does not provide solidsafter about 8 hours, then a stir bar can be added and the sample thenstirred overnight. A sample without precipitation can be evaporated todryness under a gentle gas stream, such as argon, nitrogen, ambient air,etc. The precipitated solids can be recovered by vacuum filtration,centrifuge filtration, or decanted as appropriate to afford the Form asindicated below.

General Method C: Slurry Procedures to Afford Formula (I) PolymorphForms

A mixture of one or more Forms (e.g., Form A or Form C) of the compoundof Formula (I) are placed in a vial equipped with a stir bar. A minimalamount of solvent (e.g., a single solvent or a mixture/solution of twoor more solvents) is added to the vial to form a heterogeneous slurry.Optionally, the vial can be sealed to prevent evaporation. The slurry isstirred for a period of time ranging from less than about an hour, toabout 6 hours, to about 12 hours, to about 24 hours, to about 2 days, toabout 4 days, to about 1 week, to about 1.5 weeks, to about 2 weeks orlonger. Aliquots can be taken during the stirring period to assess theForm of the solids using, for example, XRPD analysis. Optionally,additional solvent(s) can be added during the stirring period.Optionally, seeds of a given polymorph Form of the compound of Formula(I) can be added. In some cases, the slurry is then stirred for afurther period of time, ranging as recited above. The recovered solidscan be recovered by vacuum filtration, centrifuge filtration, ordecanted as appropriate to afford the Form as indicated below.

Example 10 Preparation of Polymorphs Form A, B, C, D, E, F, G, H, I, Jof the Compound of Formula (I) Form A

Single Solvent Crystallizations to Afford Formula (I) Form A

1. Fast Cooling Procedure From McCN: Approximately 23 mg of Formula (I)Form A was placed into a 20-mL glass vial equipped with a stir bar. Tothe vial was added a minimal amount of acetonitrile (7.4 ml) to justdissolve the solids at 70° C. The resulting solution was polish filteredthrough a 0.45 μm syringe filter into a clean preheated vial. After hotfiltration, the vial was placed in a refrigerator (4° C.) overnight.Once at 4° C., the contents of the vial were periodically scratched witha spatula to induce crystallization, and then allowed to equilibrate forapproximately 8 hours. The crystals were collected by decanting off theliquid and dried under vacuum (30 inches Hg) at ambient temperatureovernight. The dried solids were evaluated for crystallinity and form byXRPD which indicated the crystalline material was polymorph Form A.

2. Slow Cooling Procedure From McCN: Approximately 24 mg of Formula (I)Form A was placed into a 20-mL glass vial equipped with astir bar. Tothe vial was added a minimal amount of acetonitrile (8 ml) to justdissolve the solids at 70° C. The resulting solution was polish filteredthrough a 0.45 μm syringe filter into a clean preheated vial. After hotfiltration, the vial was cooled to ambient temperature at a rate of 20°C./h and allowed to equilibrate without stirring at ambient temperatureovernight. After the equilibration hold at ambient temperature, thecontents of the vial were periodically scratched with a spatula toinduce crystallization, and then allowed to equilibrate forapproximately 8 hours. The crystals were collected by decanting off theliquids and dried under vacuum (30 inches Hg) at ambient temperatureovernight. The dried solids were evaluated for crystallinity and form byXRPD which indicated the crystalline material was polymorph Form A.

3. Slow Cooling Procedure From n-Butanol: Approximately 23 mg of Formula(I) Form A was placed into a 2-dram glass vial equipped with a stir bar.To the vial was added a minimal amount of n-butanol (0.6 ml) to justdissolve the solids at 70° C. The resulting solution was polish filteredthrough a 0.45 μm syringe filter into a clean preheated vial. After hotfiltration, the vials were cooled to ambient temperature at a rate of20° C./h and allowed to equilibrate without stirring at ambienttemperature overnight. After the equilibration hold at ambienttemperature, the contents of the vial were periodically scratched with aspatula to induce crystallization, and then allowed to equilibrate forapproximately 8 hours. To further induce crystallization, a stir bar wasadded to the vial and the contents stirred overnight. The resultingcrystals were collected by filtration and dried under vacuum (30 inchesHg) at ambient temperature overnight. The dried solids were evaluatedfor crystallinity and form by XRPD which indicated the crystallinematerial was polymorph Form A.

Binary Solvent Crystallizations to Afford Formula (I) Form A

1. Fast Cooling Procedure From Acetone/DCM: Approximately 23.5 mg ofFormula (I) Form A was placed into a 2-dram glass vial equipped with astir bar. To the vial was added a minimal amount of acetone (2.6 ml) tojust dissolve the solids at 50° C. The resulting solution was polishfiltered through a 0.45 μm syringe filter into a clean preheated vial.After hot filtration, DCM (5.0 ml) was added portion-wise. After theanti-solvent addition, the vials were placed in a refrigerator (4° C.)overnight. Once at 4° C., the contents of the vial were periodicallyscratched with a spatula to induce crystallization, and then allowed toequilibrate for approximately 8 hours. The crystals were collected byfiltration and dried under vacuum (30 inches Hg) at ambient temperatureovernight. The dried solids were evaluated for crystallinity and form byXRPD which indicated the crystalline material was polymorph Form A.

2. Fast Cooling Procedure From MEK/DCM: Approximately 23 mg of Formula(I) Form A was placed into a 2-dram glass vial equipped with a stir bar.To the vial was added a minimal amount of MEK (2.2 ml) to just dissolvethe solids at 70° C. The resulting solution was polish filtered througha 0.45 μm syringe filter into a clean preheated vial. After hotfiltration, DCM (5.0 ml) was added portion-wise. After the anti-solventaddition, the vial was placed in a refrigerator (4° C.) overnight. Onceat 4° C., the contents of the vial were periodically scratched with aspatula to induce crystallization, and then allowed to equilibrate forapproximately 8 hours. The crystals were collected by filtration anddried under vacuum (30 inches Hg) at ambient temperature overnight. Thedried solids were evaluated for crystallinity and form by XRPD whichindicated the crystalline material was polymorph Form A.

3. Fast Cooling Procedure From DMF/DCM: Approximately 24 mg of Formula(I) Form A was placed into a 2-dram glass vial equipped with a stir bar.To the vial was added a minimal amount of DCM (0.2 ml) to just dissolvethe solids at 70° C. The resulting solution was polish filtered througha 0.45 μm syringe filter into a clean preheated vial. After hotfiltration, DCM (7.0 ml) was added portion-wise. After the anti-solventaddition, the vial was placed in a refrigerator (4° C.) overnight. Onceat 4° C., the contents of the vial were periodically scratched with aspatula to induce crystallization, and then allowed to equilibrate forapproximately 8 hours. The crystals were collected by filtration anddried under vacuum (30 inches Hg) at ambient temperature overnight. Thedried solids were evaluated for crystallinity and form by XRPD whichindicated the crystalline material was polymorph Form A.

4. Fast Cooling Procedure From Dioxane/DCM: Approximately 24.4 mg ofFormula (I) Form A was placed into a 2-dram glass vial equipped with astir bar. To the vial was added a minimal amount of dioxane (0.8 ml) tojust dissolve the solids at 70° C. The resulting solution was polishfiltered through a 0.45 μm syringe filter into a clean preheated vial.After hot filtration, DCM (7.0 ml) was added portion-wise. After theanti-solvent addition, the vial was placed in a refrigerator (4° C.)overnight. Once at 4° C., the contents of the vial were periodicallyscratched with a spatula to induce crystallization, and then allowed toequilibrate for approximately 8 hours. The crystals were collected byfiltration and dried under vacuum (30 inches Hg) at ambient temperatureovernight. The dried solids were evaluated for crystallinity and form byXRPD which indicated the crystalline material was polymorph Form A.

5. Slow Cooling Procedure From Acetone/DCM: Approximately 22 mg ofFormula (I) Form A was placed into a 2-dram glass vial equipped with astir bar. To the vial was added a minimal amount of acetone (2.5 ml) tojust dissolve the solids at 50° C. The resulting solution was polishfiltered through a 0.45 μm syringe filter into a clean preheated vial.After hot filtration, DCM (5.0 ml) was added portion-wise. After theanti-solvent addition, the vial was cooled to ambient temperature at arate of 20° C./h and allowed to equilibrate without stirring at ambienttemperature overnight. After the equilibration hold at ambienttemperature, the contents of the vial were periodically scratched with aspatula to induce crystallization, and then allowed to equilibrate forapproximately 8 hours. To further induce crystallization, a stir bar wasadded to the vial and the contents stirred overnight. The resultingcrystals were collected by filtration and dried under vacuum (30 inchesHg) at ambient temperature overnight. The dried solids were evaluatedfor crystallinity and form by XRPD which indicated the crystallinematerial was polymorph Form A.

6. Slow Cooling Procedure From MEK/DCM: Approximately 23.4 mg of Formula(I) Form A was placed into a 2-dram glass vial equipped with a stir bar.To the vial was added a minimal amount of MEK (2.2 ml) to just dissolvethe solids at 70° C. The resulting solution was polish filtered througha 0.45 μm syringe filter into a clean preheated vial. After hotfiltration, DCM (5.0 ml) was added portion-wise. After the anti-solventaddition, the vial was cooled to ambient temperature at a rate of 20°C./h and allowed to equilibrate without stirring at ambient temperatureovernight. After the equilibration hold at ambient temperature, thecontents of the vial were periodically scratched with a spatula toinduce crystallization, and then allowed to equilibrate forapproximately 8 hours. The resulting crystals were collected byfiltration and dried under vacuum (30 inches Hg) at ambient temperatureovernight. The dried solids were evaluated for crystallinity and form byXRPD which indicated the crystalline material was polymorph Form A.

7. Slow Cooling Procedure From Dioxane/DCM: Approximately 24 mg ofFormula (I) Form A was placed into a 2-dram glass vial equipped with astir bar. To the vial was added a minimal amount of dioxane (0.8 ml) tojust dissolve the solids at 70° C. The resulting solution was polishfiltered through a 0.45 μm syringe filter into a clean preheated vial.After hot filtration, DCM (7.0 ml) was added portion-wise. After theanti-solvent addition, the vial was cooled to ambient temperature at arate of 20° C./h and allowed to equilibrate without stirring at ambienttemperature overnight. After the equilibration hold at ambienttemperature, the contents of the vial were periodically scratched with aspatula to induce crystallization, and then allowed to equilibrate forapproximately 8 hours. To further induce crystallization, a stir bar wasadded to the vial and the contents stirred overnight. The resultingcrystals were collected by filtration and dried under vacuum (30 inchesHg) at ambient temperature overnight. The dried solids were evaluatedfor crystallinity and form by XRPD which indicated the crystallinematerial was polymorph Form A.

8. Slow Cooling Procedure From DMF/DCM: Approximately 23.5 mg of Formula(I) Form A was placed into a 2-dram glass vial equipped with astir bar.To the vial was added a minimal amount of DMF (0.2 ml) to just dissolvethe solids at 70° C. The resulting solution was polish filtered througha 0.45 μm syringe filter into a clean preheated vial. After hotfiltration, DCM (7.0 ml) was added portion-wise. After the anti-solventaddition, the vial was cooled to ambient temperature at a rate of 20°C./h and allowed to equilibrate without stirring at ambient temperatureovernight. After the equilibration hold at ambient temperature, thecontents of the vial were periodically scratched with a spatula toinduce crystallization, and then allowed to equilibrate forapproximately 8 hours. To further induce crystallization, a stir bar wasadded to the vial and the contents stirred overnight. To further inducecrystallization, the contents of the vial were concentrated under agentle stream of nitrogen to near dryness. The resulting crystals werecollected by filtration and dried under vacuum (30 inches Hg) at ambienttemperature overnight. The dried solids were evaluated for crystallinityand form by XRPD which indicated the crystalline material was polymorphForm A.

Slurry Procedure to Afford Formula (I) Form A

1. Procedure from CH₂Cl₂ and from IPA: Form C (1 g) was slurried in fivevolumes of dichloromethane. After holding for 15 hours, filtration, anddrying, Form A was isolated in 82% yield. Scale-up was performed on a 20g scale with a water-wet cake of Form C to yield Form A in 92% yield.Drying at 70° C. for six days indicated no degradation in chemical orchiral purity. Slurrying dry Form C in isopropyl alcohol using a similarmethod also yielded Form A.

2. Procedure for Competitive Slurry Experiment (using forms A, B and C):Competitive slurries were performed by charging approximately a 50/50mixture of Forms A and C (11.2 mg of Form A and 11.7 mg Form C) to a1-dram glass vial equipped with a glass stir bar. To the vial was added600 L of McCN. The vial cap was wrapped with parafilm to preventevaporation. The slurry was stirred for 1 day and an aliquot was taken.The contents of the vial were allowed to stir for an additional week andanother aliquot was taken. Both aliquots were centrifuge filtered forfive minutes at 8000 RPM. XRPD analysis was performed on the solids fromeach aliquot to show that the Formula (I) had converted to Form A atboth time points. After the one week aliquot was taken, an additional300 μL of acetonitrile was added to the remaining slurry and allowed toequilibrate for one day. The slurry was then seeded with approximately3.2 mg of Form B and allowed to equilibrate for an additional threedays. The solids were isolated by centrifuge filtration (5 minutes at8000 RPM) and dried over night under vacuum. The dried solids wereevaluated for crystallinity and form by XRPD which indicated thecrystalline material was polymorph Form A.

3. Procedure for Competitive Slurry Experiment (using forms A, C, D, andE): Competitive slurries were performed by charging an approximatelyequal mixture of each form (7.8 mg of Form A, 7.7 mg Form C, 7.7 mg ofForm D, and 8.2 mg of Form E) to a 1-dram glass vial equipped with aglass stir bar. To the vial was added 1 ml of 2-propanol. The vial capwas wrapped with parafilm to prevent evaporation. The slurry was mixedfor 1 day and an aliquot was taken. The contents of the vial wereallowed to stir for an additional week and another aliquot was taken.Both aliquots were centrifuge filtered for five minutes at 8000 RPM.XRPD analysis was performed on the solids from each aliquot to show thatthe Formula (I) had converted to Form A at both time points. After theone week aliquot was taken, the remaining solids were isolated bycentrifuge filtration (5 minutes at 8000 RPM) and dried over night undervacuum. The dried solids were evaluated for crystallinity and form byXRPD which indicated the crystalline material was polymorph Form A.

Form B

To a pan for a thermogravimetric analysis (TGA) instrument was loaded15-20 mg of Formula (I) Form A, Form C can also be used in this process.The crystalline sample was rapidly heated to 250° C. and held at thattemperature inside the TGA instrument for 5 minutes. After the hold wascomplete, the sample was rapidly cooled to room temperature as fast aspossible. The resulting sample was evaluated for crystallinity and formby XRPD which indicated the crystalline material was polymorph Form B.

Form C

Binary Solvent Crystallizations to Afford Formula (I) Form C

Using the General Method B of Example 9, the following experimentsdetailed in Tables 1 and 2 were performed to afford Formula (I) Form C.Table 1 experiments were conducted using the fast cooling procedure,while Table 2 experiments were conducted using the slow coolingprocedure.

TABLE 1 Fast Cooling Procedure Water Formula Primary Anti-Precipitation/ (I) Solvent solvent Temp Isolation (mg) (mL) (mL) (° C.)(scr = scratch) Form 24.3 EtOH (0.9) 3.00 70 ppt/filter C 24.3 IPA (0.6)2.00 70 ppt/filter C 24.2 THF (1.5) 6.50 60 ppt/filter C 23.4 Acetone(2.5) 5.00 50 scr/ppt/filter C 23.5 Dioxane (0.8) 3.00 70 ppt/filter C24.2 NMP (0.2) 0.90 70 ppt/filter C 24.2 DME (2.5) 5.00 70scr/ppt/filter C 23.7 DMF (0.2) 0.57 70 ppt/filter C

TABLE 2 Slow Cooling Procedure Water Formula Primary Anti-Precipitation/ (I) Solvent solvent Temp Isolation (mg) (mL) (mL) (° C.)(scr = scratch) Form 23.1 EtOH (0.9) 2.60 70 ppt/filter C 23.4 IPA (0.6)2.00 70 ppt/filter C 23.7 THF (1.5) 6.00 60 scr/filter C 23.7 Acetone(2.5) 5.00 50 scr/filter C 24.5 Dioxane (0.8) 2.70 70 ppt/filter C 23.1NMP (0.4) 1.42 70 ppt/filter C 23.4 DME (2.5) 5.00 70 scr/filter C 25.3DMF (0.2) 0.41 70 ppt/filter C

Slurry Procedures to Afford Formula (I) From C

1. Procedure for Competitive Slurry Experiment (using forms A, C, D, andE): Competitive slurries were performed by charging an approximatelyequal mixture of each form (7.9 mg of Form A, 7.8 mg Form C, 7.8 mg ofForm D, and 8.1 mg of Form E) to a 1-dram glass vial equipped with aglass stir bar. To the vial was added 1 ml of water. The vial cap waswrapped with parafilm to prevent evaporation. The slurry was mixed for 1day and an aliquot was taken. The contents of the vial were allowed tostir for an additional week and another aliquot was taken. Both aliquotswere centrifuge filtered for five minutes at 8000 RPM. XRPD analysis wasperformed on the solids to show that the Formula (I) had converted toForm C at both timepoints. After the one week aliquot was taken, theremaining solids were isolated by centrifuge filtration (5 minutes at8000 RPM) and dried overnight under vacuum. The dried solids wereevaluated for crystallinity and form by XRPD which indicated thecrystalline material was polymorph Form C.

2. Procedure for Competitive Slurry Experiment (using forms B and C):Approximately 4.9 mg of Form C was weighed into a 1 dram vial equippedwith a magnetic stir bar. To this vial was added 0.3 mL of water to forma slurry which was allowed to equilibrate for approximately 24 hours atambient temperature. An equal amount (approximately 5.4 mg) of Form Bwas added to the vial and the slurry was allowed to equilibrate for fourdays at ambient temperature. The resulting solids were isolated bycentrifuge filtration (5 minutes at 8000 RPM) and dried over night undervacuum. The dried solids were evaluated for crystallinity and form byXRPD which indicated the crystalline material was polymorph Form C.

3. Procedure for Competitive Slurry Experiment (using forms A, B and C):Competitive slurries were performed by charging approximately a 50/50mixture of Forms A and C (10.6 mg of Form A and 12 mg Form C) to a1-dram glass vial equipped with a glass stir bar. To the vial was added600 μL of a 50/50 v/v solution of water and ethanol. The vial cap waswrapped with parafilm to prevent evaporation. The slurry was mixed for 1day and an aliquot was taken. The contents of the vial were allowed tostir for an additional week, and another aliquot was taken. Bothaliquots were centrifuge filtered for five minutes at 8000 RPM. XRPDanalysis was performed on the solids to show that all the Formula (I)had converted to Form C at both timepoints. After the one week aliquotwas taken, an additional 300 μL of a 50/50 v/v solution of water andethanol was added to the remaining slurry and allowed to equilibrate forone day. The slurries were then seeded with approximately 3.6 mg of FormB and allowed to equilibrate for an additional three days beforeisolation by centrifuge filtration (5 minutes at 8000 RPM). The solidswere dried over night under vacuum at ambient temperature. The driedsolids were evaluated for crystallinity and form by XRPD which indicatedthe crystalline material was polymorph Form C.

4. A 22 L round bottom flask was charged with Form A of(S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one(1.20 kg) in 1.2 L of isopropyl alcohol and 12 L of DI water, andstirred at 20±5° C. After stirring for 3 hours, the analysis of a sampleby XRPD showed that the sample was Form C. The mixture was filteredthrough a Buchner funnel equipped with a shark skin filter paper, whichwas then rinsed with DI water (6 L) and heptanes (3.6 L). The cake wasconditioned for 1 hour, and dried at 50° C. in a vacuum oven to constantweight to afford a compound of Formula (I) as Form C (1.18 kg) in 98%yield. Additional samples of Form C were prepared starting with Form Aof(S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-oneusing the following reaction condition variations to this procedure asshown in Table 3:

TABLE 3 Purity Conditions (AUC) Yield 1 Reslurry in EtOH 99.34%  40% (16vol) at 70° C. 2 Recrystallize in EtOH/water 99.63% 42.6% (9/1 vol) from65 to 21° C. 3 Recrystallize in EtOH/water 99.64%  52% (7/1 vol) from 65to 21° C. 4 Recrystallize in EtOH/water 99.54%  77% (7/4 vol) from 82 to21° C. 5 Recrystallize in EtOH/water 99.40% 77.4% (9/7 vol) from 82 to21° C. 6 Recrystallize in EtOH/water 99.07% 90.4% (7/10 vol) from 82 to21° C.

Form D

Single Solvent Crystallizations to Afford Formula (I) Form D

1. Fast Cooling Procedure from Tetrahydrofuran (THF): Approximately 23mg of Formula (I) Form A was placed into a 2-dram glass vial equippedwith a stir bar. To the vial was added a minimal amount of THF (1.2 ml)to just dissolve the solids at 60° C. The resulting solution was polishfiltered through a 0.45 μm syringe filter into a clean preheated vial.After hot filtration, the vials were placed in a refrigerator (4° C.)overnight. Once at 4° C., the contents of the vial were periodicallyscratched with a spatula to induce crystallization, and then allowed toequilibrate for approximately 8 hour. The crystals were collected bydecanting off the liquids and dried under vacuum (30 inches Hg) atambient temperature overnight. The dried solids were evaluated forcrystallinity and form by XRPD which indicated the crystalline materialwas polymorph Form D.

2. Fast Cooling Procedure from 2-Butanone (MEK): Approximately 23 mg ofFormula (I) Form A was placed into a 2-dram glass vial equipped with astir bar. To the vial was added a minimal amount of MEK (2.0 ml) to justdissolve the solids at 70° C. The resulting solution was polish filteredthrough a 0.45 μm syringe filter into a clean preheated vial. After hotfiltration, the vials were placed in a refrigerator (4° C.) overnight.Once at 4° C. the contents of the vial were periodically scratched witha spatula to induce crystallization, and then allowed to equilibrate forapproximately 8 hours. The crystals were collected by decanting off theliquids and dried under vacuum (30 inches Hg) at ambient temperatureovernight. The dried solids were evaluated for crystallinity and form byXRPD which indicated the crystalline material was polymorph Form D.

3. Fast Cooling Procedure from Dioxane: Approximately 25 mg of Form Awas placed into a 2-dram glass vial equipped with a stir bar. To thevial was added a minimal amount of THF (1.5 ml) to just dissolve thesolids at 70° C. The resulting solution was polish filtered through a0.45 μm syringe filter into a clean preheated vial. After hotfiltration, the vial was placed in a refrigerator (4° C.) overnight.Once at 4° C., the contents of the vial were periodically scratched witha spatula to induce crystallization, and then allowed to equilibrate forapproximately 8 hours. To further induce crystallization, the contentsof the vial were evaporated to near dryness under a gentle stream ofnitrogen. The crystals were collected by decanting off any remainingliquids and dried under vacuum (30 inches Hg) at ambient temperatureovernight. The dried solids were evaluated for crystallinity and form byXRPD which indicated the crystalline material was polymorph Form D.

4. Fast Cooling Procedure from N,N-dimethylformamide (DMF):Approximately 23.5 mg of Formula (I) Form A was placed into a 2-dramglass vial equipped with a stir bar. To the vial was added a minimalamount of DMF (0.3 ml) to just dissolve the solids at 70° C. Theresulting solution was polish filtered through a 0.45 μm syringe filterinto a clean preheated vial. After hot filtration, the vial was placedin a refrigerator (4° C.) overnight. Once at 4° C., the contents of thevial were periodically scratched with a spatula to inducecrystallization, and then allowed to equilibrate for approximately 8hours. To further induce crystallization, the contents of the vial wereevaporated to near dryness under a gentle stream of nitrogen. Thecrystals were collected by decanting off any remaining liquids and driedunder vacuum (30 inches Hg) at ambient temperature overnight. The driedsolids were evaluated for crystallinity and form by XRPD which indicatedthe crystalline material was polymorph Form D.

5. Slow Cooling Procedure from Tetrahydrofuran (THF): Approximately 25mg of Formula (I) Form A was placed into a 2-dram glass vial equippedwith a stir bar. To the vial was added a minimal amount of THF (1.1 ml)to just dissolve the solids at 60° C. The resulting solution was polishfiltered through a 0.45 μm syringe filter into a clean preheated vial.After hot filtration, the vial was cooled to ambient temperature at arate of 20° C./h and allowed to equilibrate without stirring at ambienttemperature overnight. After the equilibration hold at ambienttemperature, the contents of the vial were periodically scratched with aspatula to induce crystallization, and then allowed to equilibrate forapproximately 8 hours. The crystals were collected by decanting off theliquids and dried under vacuum (30 inches Hg) at ambient temperatureovernight. The dried solids were evaluated for crystallinity and form byXRPD which indicated the crystalline material was polymorph Form D.

6. Slow Cooling Procedure from 2-Butanone (MEK): Approximately 24.5 mgof Formula (I) Form A was placed into a 2-dram glass vial equipped witha stir bar. To the vial was added a minimal amount of MEK (4 ml) to justdissolve the solids at 70° C. The resulting solution was polish filteredthrough a 0.45 μm syringe filter into a clean preheated vial. After hotfiltration, the vials were cooled to ambient temperature at a rate of20° C./h and allowed to equilibrate without stirring at ambienttemperature overnight. After the equilibration hold at ambienttemperature, the contents of the vial were periodically scratched with aspatula to induce crystallization, and then allowed to equilibrate forapproximately 8 hours. The crystals were collected by decanting off theliquids and dried under vacuum (30 inches Hg) at ambient temperatureovernight. The dried solids were evaluated for crystallinity and form byXRPD which indicated the crystalline material was polymorph Form D.

7. Slow Cooling Procedure from Dioxane: Approximately 24 mg of Formula(I) Form A was placed into a 2-dram glass vial equipped with a stir bar.To the vial was added a minimal amount of dioxane (1.1 ml) to justdissolve the solids at 70° C. The resulting solution was polish filteredthrough a 0.45 μm syringe filter into a clean preheated vial. After hotfiltration, the vial was cooled to ambient temperature at a rate of 20°C./h and allowed to equilibrate without stirring at ambient temperatureovernight. After the equilibration hold at ambient temperature, thecontents of the vial were periodically scratched with a spatula toinduce crystallization, and then allowed to equilibrate forapproximately 8 hours. The crystals were collected by decanting off theliquids and dried under vacuum (30 inches Hg) at ambient temperatureovernight. The dried solids were evaluated for crystallinity and form byXRPD which indicated the crystalline material was polymorph Form D.

Binary Solvent Crystallizations to Afford Formula (I) Form D

Using the General Method B of Example 9, the following experimentsdetailed in Tables 4 and 5 were performed to afford Formula (I) Form C.Table 4 experiments were conducted using the fast cooling procedure,while Table 5 experiments were conducted using the slow coolingprocedure.

TABLE 4 Fast Cooling Procedure Precipitation/ Formula Primary Anti-Isolation (I) Solvent solvent Temp (scr = scratch; (mg) (mL) (mL) (° C.)evp = evaporation) Form 24.7 THF (1.5) MTBE (3.0) 60 filter D 22.5Dioxane (0.65) MTBE (1.5) 70 filter D 24.2 DMF (0.2) MTBE (1.6) 70scr/filter D 23.5 THF (1.5) DCM (6.0) 60 scr/evp/decant D 23.6 IPA (0.6)Toluene (6.5) 70 scr/evp/decant D 23.7 THF (1.5) Toluene (5.0) 60scr/filter D 23.9 DMF (0.2) Toluene (3.0) 70 scr/filter D

TABLE 5 Slow Cooling Procedure Precipitation/ Formula Primary Anti-Isolation (I) Solvent solvent Temp (scr = scratch; (mg) (mL) (mL) (° C.)evp = evaporation) Form 22.9 MEK (2.2) MTBE (2.0) 70 filter D 25.3 DMF(0.2) MTBE (1.4) 70 decant D 24.1 THF (1.5) DCM (6.0) 60scr/stir/evp/decant D 23.3 DME (2.6) DCM (5.0) 70 scr/stir/evp/filter D24.1 IPA (0.7) Toluene (6.0) 70 scr/stir/evp/decant D 24.4 NNP (0.2)Toluene (7.0) 60 filter D 24 DME (2.5) Toluene (5.0) 70 scr/stir/filterD

Slurry Procedures to Afford Formula (I) Form D

1. Approximately 122 mg of Formula (I), Form A, was weighed into 8 mLvial equipped with a magnetic stir bar. To the vial was added 3.0 mL of2-butanone (MEK) to form a slurry. The contents of the vial were heatedto 50° C., and held for approximately 1.5 hours. After the hold, thecontents of the vial were slowly cooled at a rate of 20° C./h to roomtemperature. The mixture was then allowed to stir overnight. The productwas isolated by vacuum filtration, and dried over night in vacuo. Thedried solids were evaluated for crystallinity and form by XRPD whichindicated the crystalline material was polymorph Form D.

2. Procedure for Competitive Slurry Experiment (using forms A, B and C):Competitive slurries were performed by charging approximately a 50/50mixture of Forms A and C (10.3 mg of Form A and 11.7 mg Form C) to a1-dram glass vial equipped with a glass stir bar. To the vial was added600 μL of MEK. The vial cap was wrapped with parafilm to preventevaporation. The slurry was mixed for 1 day and an aliquot was taken.The contents of the vial were allowed to stir for an additional week,and another aliquot was taken. Both aliquots were centrifuge filteredfor five minutes at 8000 RPM. XRPD analysis was performed on the solidsto show that the Formula (I) had converted to Form D at both timepoints.After the one week aliquot was taken, an additional 300 μL of MEK wasadded to the remaining slurry and allowed to equilibrate for one day.The slurries were then seeded with approximately 4.5 mg of Form B andallowed to equilibrate for an additional three days before isolation bycentrifuge filtration (5 minutes at 8000 RPM). The solids were driedover night under vacuum at ambient temperature. The dried solids wereevaluated for crystallinity and form by XRPD which indicated thecrystalline material was polymorph Form D.

3. Procedure for Competitive Slurry Experiment (using forms B and D):Approximately 6 mg of Formula (I) Form D was weighed into a 1 dram vialequipped with magnetic stir bar. To this vial was added 0.3 mL of MEK toform a slurry and allowed to equilibrate for approximately 24 hours atambient temperature. An equal amount (approximately 6 mg) of Form B wasadded to the vial and allowed to equilibrate for four days at ambienttemperature. The resulting solids were isolated by centrifuge filtration(5 minutes at 8000 RPM) and dried over night under vacuum. The driedsolids were evaluated for crystallinity and form by XRPD which indicatedthe crystalline material was polymorph Form D.

Forms A, C, and D

Slurry Procedures to Afford Formula (I) Forms A, C, and D

Using General Method C of Example 9, the following experiments detailedin Table 6 were performed to afford the polymorph Form of the compoundof Formula (I) as indicated.

TABLE 6 Formula Initial Amount Temp. Observation/ Final (I) (mg) FormSolvent (mL) (° C.) Time Isolation Form 1 15.4 Form A water 0.75 RT 14days filter C 2 26.0 Form A EtOH 0.75 RT 14 days filter A 3 19.5 Form AMEK 0.75 RT 14 days filter D 4 15.9 Form A t-AmOH 0.50 RT 14 daysfilter, n/a no solids obtained 5 19.5 Form A MeCN 0.75 RT 14 days filterA 6 17.6 Form A EtOAc 0.75 RT 14 days filter Amorphous 7 16.0 Form Cwater 0.6 RT 14 days filter C 8 15.6 Form C EtOH 0.6 RT 14 days filter,n/a no solids obtained 9 15.1 Form C MEK 0.6 RT 14 days filter D 10 17.4Form C EtOAc 0.6 RT 14 days filter Amorphous 11 14.0 Form C MeCN 0.6 RT14 days filter A 12 10.9 Form D water 0.6 RT 14 days filter C 13 3.5 +3.7 Form D EtOH 0.3 RT 14 days filter, n/a no solids obtained 14 6.7Form D MeCN 0.3 RT 14 days filter A 15 9.2 Form E water 0.5 RT 17 daysfilter C 16 10.5 Form E MEK 0.5 RT 17 days filter D 17 8 Form E MeCN 0.5RT 17 days filter A

Form E

Single Solvent Crystallization to Afford Formula (I) Form E

Slow Cooling Procedure from Methanol: Approximately 23.5 mg of Formula(I) Form A was placed into a 2-dram glass vial equipped with astir bar.To the vial was added a minimal amount of methanol (0.53 ml) to justdissolve the solids at 60° C. The resulting solution was polish filteredthrough a 0.45 μm syringe filter into a clean preheated vial. After hotfiltration, the vials were cooled to ambient temperature at a rate of20° C./h and allowed to equilibrate without stirring at ambienttemperature overnight. After the equilibration hold at ambienttemperature, the crystals were collected by decanting off the liquidsand dried under vacuum (30 inches Hg) at ambient temperature overnight.The dried solids were evaluated for crystallinity and form by XRPD whichindicated the crystalline material was polymorph Form E.

Binary Solvent Crystallizations to Afford Formula (I) Form E

1. Fast Cooling Procedure from Methanol/Water. Approximately 23.4 mg ofFormula (I) Form A was placed into a 2-dram glass vial equipped with astir bar. To the vial was added a minimal amount of methanol (0.6 ml) tojust dissolve the solids at 60° C. The resulting solution was polishfiltered through a 0.45 μm syringe filter into a clean preheated vial.After hot filtration, water (0.85 ml) was added portion-wise. After theanti-solvent addition, the vial was placed in a refrigerator (4° C.)overnight. The crystals were collected by filtration and dried undervacuum (30 inches Hg) at ambient temperature overnight. The dried solidswere evaluated for crystallinity and form by XRPD which indicated thecrystalline material was polymorph Form E.

2. Slow Cooling Procedure from Methanol/Water Approximately 23 mg ofFormula (I) Form A was placed into a 2-dram glass vial equipped with astir bar. To the vial was added a minimal amount of methanol (0.6 ml) tojust dissolve the solids at 60° C. The resulting solution was polishfiltered through a 0.45 μm syringe filter into a dean preheated vial.After hot filtration, water (0.83 ml) was added portion-wise. After theanti-solvent addition, the vial was cooled to ambient temperature at arate of 20° C./h and allowed to equilibrate without stirring at ambienttemperature overnight. The resulting crystals were collected byfiltration and dried under vacuum (30 inches Hg) at ambient temperatureovernight. The dried solids were evaluated for crystallinity and form byXRPD which indicated the crystalline material was polymorph Form E.

Slurry Procedures to Afford Formula (I) Form E

1. Approximately 127 mg of Formula (I), Form A, was weighed into an 8 mLvial equipped with a magnetic stir bar. To the vial was added 3.0 mL ofmethanol to form a slurry. The contents of the vial was heated to 50°C., and held for approximately 1.5 hours. After the hold, the contentsof the vial were slowly cooled at a rate of 20° C./h to roomtemperature. The mixture was then allowed to stir over night. Theproduct was isolated by vacuum filtration, and dried over night invacuo. The dried solids were evaluated for crystallinity and form byXRPD which indicated the crystalline material was polymorph Form E.

2. Approximately 5.6 mg of Formula (I) Form E was weighed into a 1 dramvial equipped with a magnetic stir bar. To this vial was added 0.3 mL ofmethanol to form a slurry and the slurry was allowed to equilibrate forapproximately 24 hours at ambient temperature. An equal amount(approximately 5.7 mg) of Form B was added to the vial and allowed toequilibrate for four days at ambient temperature. The resulting solidswere isolated by centrifuge filtration (5 minutes at 8000 RPM) and driedover night under vacuum. The dried solids were evaluated forcrystallinity and form by XRPD which indicated the crystalline materialwas polymorph Form E.

Form F

Binary Solvent Crystallizations to Afford Formula (I) Form F

1. Fast Cooling Procedure from NMP/MTBE: Approximately 23 mg of Formula(I) Form A was placed into a 2-dram glass vial equipped with a stir bar.To the vial was added a minimal amount of NMP (0.2 ml) to just dissolvethe solids at 70° C. The resulting solution was polish filtered througha 0.45 μm syringe filter into a clean preheated vial. After hotfiltration, MTBE (1.0 ml) was added portion-wise. After the anti-solventaddition, the vial was placed in a refrigerator (4° C.) overnight. Thecrystals were collected by filtration and dried under vacuum (30 inchesHg) at ambient temperature overnight. The dried solids were evaluatedfor crystallinity and form by XRPD which indicated the crystallinematerial was polymorph Form F.

2. Slow Cooling Procedure from NMP/MTBE: Approximately 23 mg of Formula(I) Form A was placed into a 2-dram glass vial equipped with astir bar.To the vial was added a minimal amount of NMP (0.2 ml) to just dissolvethe solids at 70° C. The resulting solution was polish filtered througha 0.45 μm syringe filter into a clean preheated vial. After hotfiltration, MTBE (1.0 ml) was added portion-wise. After the anti-solventaddition, the vial was cooled to ambient temperature at a rate of 20°C./h and allowed to equilibrate without stirring at ambient temperatureovernight. The resulting crystals were collected by filtration and driedunder vacuum (30 inches Hg) at ambient temperature overnight. The driedsolids were evaluated for crystallinity and form by XRPD which indicatedthe crystalline material was polymorph Form F.

Form G

Binary Solvent Crystallizations to Afford Formula (I) Form G

1. Fast Cooling Procedure from ethanol/MTBE: Approximately 24.3 mg ofFormula (I) Form A was placed into a 2-dram glass vial equipped with astir bar. To the vial was added a minimal amount of ethanol (0.78 ml) tojust dissolve the solids at 70° C. The resulting solution was polishfiltered through a 0.45 μm syringe filter into a clean preheated vial.After hot filtration, MTBE (7.0 ml) was added portion-wise. After theanti-solvent addition, the vial was placed in a refrigerator (4° C.)overnight. Once at 4° C., the contents of the vial were periodicallyscratched with a spatula to induce crystallization, and then allowed toequilibrate for approximately 8 hours. The crystals were collected bydecanting any liquids and dried under vacuum (30 inches Hg) at ambienttemperature overnight. The dried solids were evaluated for crystallinityand form by XRPD which indicated the crystalline material was polymorphForm G.

2. Fast Cooling Procedure with IPA/MTBE: Approximately 23.7 mg ofFormula (I) Form A was placed into a 2-dram glass vial equipped with astir bar. To the vial was added a minimal amount of IPA (0.60 ml) tojust dissolve the solids at 70° C. The resulting solution was polishfiltered through a 0.45 μm syringe filter into a clean preheated vial.After hot filtration, MTBE (6.0 ml) was added portion-wise. After theanti-solvent addition, the vial was placed in a refrigerator (4° C.)overnight. Once at 4° C., the contents of the vial were periodicallyscratched with a spatula to induce crystallization, and then allowed toequilibrate for approximately 8 hours. The crystals were collected byvacuum filtration and dried under vacuum (30 inches Hg) at ambienttemperature overnight. The dried solids were evaluated for crystallinityand form by XRPD which indicated the crystalline material was polymorphForm G.

3. Fast Cooling Procedure with Methanol/MTBE: Approximately 24 mg ofFormula (I) Form A was placed into a 2-dram glass vial equipped with astir bar. To the vial was added a minimal amount of methanol (0.6 ml) tojust dissolve the solids at 60° C. The resulting solution was polishfiltered through a 0.45 μm syringe filter into a clean preheated vial.After hot filtration, MTBE (6.0 ml) was added portion-wise. After theanti-solvent addition, the vials were placed in a refrigerator (4° C.)overnight. Once at 4° C., the contents of the vial were periodicallyscratched with a spatula to induce crystallization, and then allowed toequilibrate for approximately 8 hours. The crystals were collected bydecanting any liquids and dried under vacuum (30 inches Hg) at ambienttemperature overnight. The dried solids were evaluated for crystallinityand form by XRPD which indicated the crystalline material was polymorphForm G.

Form H

Binary Solvent Crystallization to Afford Formula (I) Form H

Slow Cooling Procedure from Dioxane/MTBE: Approximately 23.2 mg ofFormula (I) Form A was placed into a 2-dram glass vial equipped with astir bar. To the vial was added a minimal amount of dioxane (0.6 ml) tojust dissolve the solids at 70° C. The resulting solution was polishfiltered through a 0.45 μm syringe filter into a dean preheated vial.After hot filtration, MTBE (1.0 ml) was added portion-wise. After theanti-solvent addition, the vial was cooled to ambient temperature at arate of 20° C./h and allowed to equilibrate without stirring at ambienttemperature overnight. The resulting crystals were collected byfiltration and dried under vacuum (30 inches Hg) at ambient temperatureovernight. The dried solids were evaluated for crystallinity and form byXRPD which indicated the crystalline material was polymorph Form H.

Binary Solvent Crystallizations to Afford Formula (I) Form I

1. Slow Cooling Procedure from Acetone/Toluene: Approximately 23.3 mg ofFormula (I) Form A was placed into a 2-dram glass vial equipped with astir bar. To the vial was added a minimal amount of acetone (2.5 ml) tojust dissolve the solids at 50° C. The resulting solution was polishfiltered through a 0.45 μm syringe filter into a clean preheated vial.After hot filtration, toluene (5.0 ml) was added portion-wise. After theanti-solvent addition, the vial was cooled to ambient temperature at arate of 20° C./h and allowed to equilibrate without stirring at ambienttemperature overnight. The resulting crystals were collected byfiltration and dried under vacuum (30 inches Hg) at ambient temperatureovernight. The dried solids were evaluated for crystallinity and form byXRPD which indicated the crystalline material was polymorph Form I.

2. Slow Cooling Procedure with MEK/Toluene: Approximately 24.1 mg ofFormula (I) Form A was placed into a 2-dram glass vial equipped with astir bar. To the vial was added a minimal amount of MEK (2.1 ml) to justdissolve the solids at 70° C. The resulting solution was polish filteredthrough a 0.45 μm syringe filter into a clean preheated vial. After hotfiltration, toluene (6.0 ml) was added portion-wise. After theanti-solvent addition, the vial was cooled to ambient temperature at arate of 20° C./h and allowed to equilibrate without stirring at ambienttemperature overnight. The resulting crystals were collected byfiltration and dried under vacuum (30 inches Hg) at ambient temperatureovernight. The dried solids were evaluated for crystallinity and form byXRPD which indicated the crystalline material was polymorph Form I.

3. Slow Cooling Procedure with Dioxane/Toluene: Approximately 24.5 mg ofFormula (I) Form A was placed into a 2-dram glass vial equipped with astir bar. To the vial was added a minimal amount of dioxane (0.8 ml) tojust dissolve the solids at 70° C. The resulting solution was polishfiltered through a 0.45 μm syringe filter into a clean preheated vial.After hot filtration, toluene (1.0 ml) was added portion-wise. After theanti-solvent addition, the vials were cooled to ambient temperature at arate of 20° C./h and allowed to equilibrate without stirring at ambienttemperature overnight. The resulting crystals were collected byfiltration and dried under vacuum (30 inches Hg) at ambient temperatureovernight. The dried solids were evaluated for crystallinity and form byXRPD which indicated the crystalline material was polymorph Form I.

Form J

Binary Solvent Crystallizations to Afford Formula (I) Form J

Slow Cooling Procedure with DMF/Toluene: Approximately 24.2 mg ofFormula (I) Form A was placed into a 2-dram glass vial equipped with astir bar. To the vial was added a minimal amount of DMF (0.2 ml) to justdissolve the solids at 70° C. The resulting solution was polish filteredthrough a 0.45 μm syringe filter into a clean preheated vial. After hotfiltration, toluene (2.0 ml) was added portion-wise. After theanti-solvent addition, the vials were cooled to ambient temperature at arate of 20° C./h and allowed to equilibrate without stirring at ambienttemperature overnight. The resulting crystals were collected byfiltration and dried under vacuum (30 inches Hg) at ambient temperatureovernight. The dried solids were evaluated for crystallinity and form byXRPD which indicated the crystalline material was polymorph Form J.

Example 11 Preparation of Amorphous Compound of Formula (I)

To polymorph Form A of the compound of Formula (I) (2.0 g) was added 50mL of t-butanol and 25 mL of water. The mixture was heated with stirringto 40° C. for 0.5 hours. After sonication for about 20 minutes, 25 mL oft-butanol was added. The mixture was then cooled to RT to give ahomogeneous solution. After filtration, the resulting solution waslyophilized for 2 days and a fluffy solid resulted. The amorphousquality of the solid was confirmed by XRPD (see FIG. 11 ), DSC and TGAanalyses.

Example 12 XRPD Studies

Using the XRPD instrument and parameters described above, the followingXRPD peaks were observed for Formula (I) Polymorph Forms A, B, C, D, E,F, G, H, I, and J. The XRPD traces for these ten polymorph forms aregiven in FIGS. 1-10 , respectively. In Table 7, peak position units are° 20. In one embodiment, a given polymorph Form can be characterized ashaving at least one of the five XRPD peaks given in Set 1 in Table 7. Inanother embodiment, the given Form can be characterized as having atleast one of the five XRPD peaks given in Set 1 in combination with atleast one of the XRPD peaks given in Set 2 in Table 7. In someembodiments, one or more peak position values can be defined as beingmodified by the term “about” as described herein. In other embodiments,any given peak position is with ±0.2 2θ (e.g., 9.6±0.2 2θ).

TABLE 7 Form A B C D E F G H I J XRPD 9.6 7.9 6.6 9.2 6.7 9.6 6.7 8.79.7 9.1 Peaks 12.2 13.4 10.4 11.4 9.3 14.0 9.5 9.2 11.4 16.4 Set 1 15.614.0 12.5 17.4 12.7 17.3 10.6 14.1 14.2 17.3 (° 2θ) 18.3 15.0 13.3 18.313.9 19.2 19.0 17.3 19.3 17.9 19.2 23.4 24.3 22.9 24.4 24.6 19.6 18.524.5 18.3 XRPD 9.1 9.5 8.8 9.8 12.4 12.4 13.4 7.1 9.2 9.4 Peaks 9.4 12.79.9 12.2 13.3 16.1 15.0 10.6 14.7 10.1 Set 2 12.4 13.6 13.4 15.8 14.316.6 15.8 11.3 15.5 10.7 (° 2Th) 14.8 14.2 15.5 16.2 15.5 17.1 17.8 11.616.7 14.0 16.3 15.7 16.9 16.8 17.4 20.8 20.7 16.2 17.3 14.3 17.7 19.019.8 18.9 18.5 21.5 21.2 18.3 18.4 15.5 21.1 22.3 21.3 19.9 22.0 22.022.8 18.8 21.4 16.9 21.9 24.2 23.6 20.0 23.9 24.3 23.8 20.3 22.9 19.924.0 24.8 25.3 24.9 24.1 25.2 24.3 21.7 29.1 24.0 26.9 26.9 27.9 29.326.4 25.4 25.6 24.7 34.1 24.7

Example 13 Differential Scanning Calorimetry (DSC) Studies

Using the DSC instrument and parameters described above, the followingDSC peaks were observed for the compound of Formula (I) polymorph FormsA, B, C, D, E, F, G, H, I, and J. The DSC thermograms for these ninepolymorph forms are given in FIGS. 12-24 , respectively, and peakpositions are given in Table 8. Further DSC data for Polymorph Forms A,B, C, D, E, F, G, H, I, and J is given in Table 9 below. Unless markedwith a {circumflex over ( )} that indicates an exothermic peak, allpeaks are endothermic.

TABLE 8 Form FIG. DSC peaks (° C.) A 12 239, 280 A 21 238, 280 B 13 281C 14 208, 254{circumflex over ( )}, 283 C 23 top about 208, about245{circumflex over ( )}, 281 C 23 bottom 206, 251{circumflex over ( )},283 D 15 260, 283 E 16 131, 263, 267{circumflex over ( )}, 282 F 17 181,260, 266{circumflex over ( )}, 282 F 24 181, 260, 266{circumflex over( )}, 282 G 18 162, 241{circumflex over ( )}, 281 H 19 128, 258, 282 I20 208, 263 J 21 121, 185, 259, 282

As observed in FIGS. 12-23 , the DSC thermograms for Polymorph Forms A,B, C, D, E, F, G, H, and J each have a endothermic peak in the about280° C. to about 282° C. range. This peak represents that upon heating,the given Form recrystallizes to Form B (see Example 10 where heatingForm A or Form C to about 250° C. then cooling affords Form B) whichthen has its characteristic endothermic peak in the about 280° C. toabout 282° C. range.

Example 14 Thermogravimetric Analysis (TGA) Studies

Using the TGA instrument and parameters described above, the followingTGA peaks summarized in Table 9 were observed for Formula (I) PolymorphForms C-J. The peaks correspond to when a weight loss (% wt) is observedat a given temperature as the sample is heated.

Example 15 Summary of Preparation and Analysis of Formula (I) PolymorphForms A-J

Table 9 summarizes non-limiting exemplary preparation techniques forFormula (I) Polymorph Forms A-J and representative analytical data asdescribed below and elsewhere.

TABLE 9 TGA Polymorph Cooling % wt loss API:Solvent Form details GeneralConditions profiles Raman DSC (temp° C.) molar ratio A anhydratestarting material, fast and Form A 236, 0 n/a slurries in IPA, slow 280EtOH, and MeCN, cooling crystallizations with DCM as anti- solvent Banhydrate isothermal hold of n/a no 281 n/a n/a Form A at 250° C.spectrum for 5 minutes C channel slurries in water, fast and Form C,204, 1.7% n/a hydrate or water as an slow generally 242{circumflex over( )},  (80° C.), anti-solvent cooling 280 0.2% (190° C.) D anhydratecrystallizations in fast and Form D, 260, 0.2% n/a MEK, also seen slowgenerally 283 (150° C.) during salt cooling formations in MEK Eanhydrate crystallizations in slow Free Form 131, 0.7% 1.0:0.06 MeOHwithout cooling E 263,  (80° C.), API:MeOH anti-solvents only267{circumflex over ( )}, 1.3% 282 (130° C.) F NMP Crystallizations infast and Free Form 181, 15.8% 1.0:0.73 Solvate NMP with MTBE slow F 260,(150° C.), API:NMP as anti-solvent cooling 266{circumflex over ( )},2.8% 282 (180° C.) G MTBE Crystallizations in fast Free Form 162, 18.5%1.0:0.87 Solvate EtOH, IPA, and cooling G 241{circumflex over ( )},(160° C.) API:MTBE MeOH with only 281 MTBE as an anti- solvent H channelcrystallization in slow consistent 128, 7.5% 1.0:0.34 MTBE dioxane withcooling with Form 258, (130° C.) API:MTBE solvate MTBE as anti- only D281 solvent only I hemi- crystallizations fast and consistent 208, 10.5%1.9:0.5  toluene with toluene as slow with Form 263 (130° C.),API:Toluene solvate anti-solvent cooling D 0.8% (200° C.) J hemi-crystallization in slow consistent 121, 10.8% 1.0:0.5  toluene DMF withtoluene cooling with Form 185, (100° C.) API:Toluene solvate asanti-solvent only D 259, 282

Example 16 Stability Studies

Polymorphs Form A and Form C were subjected to stability studies whereseveral samples of each given Form were packaged and subjected to thegiven temperature and humidity conditions as described in Table 10. Ateach time point, a sample for that study was opened and evaluated byHPLC for purity, Karl Fischer for moisture content, and XRPD forconfirming the polymorph Form. In all studies detailed in Table 10 ateach evaluation timepoint, no indication of instability of thepolymorphic Form was observed.

TABLE 10 Form Packaging Storage Conditions Evaluation Timepoints ADouble LDPE bags twist 40° C. ± 2° C./ 1, 2, 3, 6, and 12 months tied toclose inside a 75% RH ± 5% RH fiberboard drum C Primary: Double LDPEStudy 1: 5° C. ± 3° C./ For both Studies 1 and 2: bags twist tied toclose 60% RH ± 5% RH 1, 3, 6, and 9 months Secondary: Study 2: 25° C. ±2° C./ For Study 3: Polyethylene/foil bag 60% RH ± 5% RH 2 weeks, 1,month, 3 months, twist tied to close Study 3: 40° C. ± 2° C./ and 6months Outer: HDPE drum 75% RH ± 5% RH C Primary: Double LDPE Study 1:5° C. ± 3° C./ For all 3 Studies: bags twist tied to close 60% RH ± 5%RH 1, 3, and 6 months Secondary: Study 2: 25° C. ± 2° C./Polyethylene/Mylar ® 60% RH ± 5% RH bag twist tied to close Study 3: 40°C. ± 2° C./ Outer: HDPE drum 75% RH ± 5% RH C Primary: Double LDPE Study1: 5° C. ± 3° C./ For all 3 Studies: bags twist tied to close 60% RH ±5% RH 1, 3, and 6 months Secondary: Study 2: 25° C. ± 2° C./Polyethylene/foil bag 60% RH ± 5% RH twist tied to close Study 3: 40° C.± 2° C./ Outer: HDPE drum 75% RH ± 5% RH

Example 17 Dynamic Vapor Sorption Analysis

Dynamic vapor sorption (DVS) analysis was performed on polymorph FormsA, B, C, D, and E using the DVS instrument and parameters as describedabove, Form A was observed to be slightly hygroscopic and showed 0.7 wt% moisture uptake at 60% RH and 2.6 wt % moisture uptake at 90% RH.Hysteresis indicative of hemi-hydrate formation was observed, Form B wasobserved to be slightly hygroscopic and showed 1.0 wt % moisture uptakeat 60% RH and 1.7 wt % moisture uptake at 90% RH. Form C was observed tobe moderately hygroscopic, showing 4.2% moisture uptake at 60% RH and4.9% moisture uptake at 90% RH (see FIG. 30 ), Form D was observed to beslightly hygroscopic and showed 0.4 wt % moisture uptake at 60% RH and1.7 wt % moisture uptake at 90% RH, Form E was observed to be slightlyhygroscopic and showed 1.9 wt % moisture uptake at 60% RH and 2.2 wt %moisture uptake at 90% RH. Both Forms A and C were held in humiditychambers at 9% RH and 95% RH and showed no changes in Form after 1 week.

Example 18 Thermal Stability

Forms A, B, C, D, and E were held at 60° C. for 10 days followed byanalysis by XRPD. In each case, 8 mL vials were charged withapproximately 20 mg of material, with the exception of Form B for which10 mg of material was charged. Samples equilibrated in an oven for 10days. No polymorph Form changes were observed by XRPD. All Forms wereobserved to be stable.

Example 19 Grinding Stability

Forms A, C, D, and E were subjected to grinding experiments performedusing a mortar and pestle by hand. Samples were lightly grounded for 2minutes then analyzed by XRPD. Material was then returned to the mortarand pestle and grounded for an additional 3 minutes, for a total of 5minutes of grinding, and reanalyzed by XRPD, Form A was observed toremain consistent after both 2 and 5 minutes of grinding, Form C wasobserved to remain consistent after both 2 and 5 minutes of grinding.

Example 20 Summary of Examples 17-19

Table 11 summarizes non-limiting representative analytical data forFormula (I) Polymorph Forms A-E as described below and elsewhere.

TABLE 11 Thermal Grinding stability (mortar & Solubility Form NMR DVS(60° C.) pestle) (mg/mL) A consistent 0.7% @ 60% RH stable afterremained Form 0.030 (H₂O) 2.6% @ 90% RH 1 week A after 5 min. 21.800(SGF)  B consistent 1.0% @ 60% RH stable after n/a n/a 1.7% @ 90% RH 1week C consistent; 4.2% @ 60% RH stable after remained Form 0.001 (H₂O)1.9% water 4.9% @ 90% RH 1 week C after 5 min, 9.133 (SGF) by KF v. lowintensity D consistent 0.4% @ 60% RH stable after amorphous n/a 1.7% @90% RH 1 week after 2 min. E 0.5 wt % 1.9% @ 60% RH stable afteramorphous n/a MeOH 2.2% @ 90% RH 1 week after 5 min.

Example 21 Salt Screen

Salts of a compound of Formula (I) were formed with L-tartaric acid,p-toluenesulfonic acid, D-glucaronic acid, ethane-1,2-disulfonic acid(EDSA), 2-naphthalenesulfonic acid (NSA), hydrochloric acid (HCl)(monoand bis), hydrobromic acid (HBr), citric acid,naphthalene-1,5-disulfonic acid (NDSA), DL-mandelic acid, fumaric acid,sulfuric acid, maleic acid, methanesulfonic acid (MSA), benzenesulfonicacid (BSA), ethanesulfonic acid (ESA), L-malic acid, phosphoric acid,and aminoethanesulfonic acid (taurine). Various salts and the free basewere tested against various solvents for formation of crystallinesolids, as shown in FIG. 25 . Tables 12 and 13 summarize representativedata for exemplary salts of a compound of Formula (I). A compound ofFormula (I) was observed to form semi-crystalline to crystallinemono-salts with ethanc-1,2-disulfonic acid (EDSA), 2-naphthalenesulfonicacid (NSA), hydrochloric acid (HC), hydrobromic acid (HBr), citric acid,and amorphous mono-salt with naphthalene-1,5-disulfonic acid (NDSA) andan amorphous bis-salt with HC from various solvents.

TABLE 12 API:CI (ratio by TGA Counter ion Solvent Form by XRPD NMR orIC) DSC (° C.) (wt loss %) Free Form A n/a Free Form A consistent 236,242, 280 0   EDSA acetone semi-cryst 1.0:1.1 63, 210, 260, 284 1.1, 1.1MEK semi-cryst 1.0:1.1 57, 209, 259, 283 1.0 NSA acetone crystalline1.0:1.1 252 0   acetone crystalline  1.0:1.06 n/a n/a HCl MEKcrystalline 1.0:1.2 163, 177, 213  5.7, 10.0 (MEK solvate) Bis HCLIPA/IPAc amorphous 1.0:1.8 182, 215 0.5, 12.8, 6.0 NDSA MEK amorphous 1.0:0.92 96, 216, 273 6.1

TABLE 13 Solubility in water Moisture Counter (mg/mL) Sorption ion (pH)(wt % water) Comments Free 0.03 60% RH: 0.7 high melt B Form A (3.29)90% RH: 2.6 form EDSA 9.4 60% RH: 7.5 Forms (1.43) 90% RH: 28.1sticky/oily material in water NSA 0.05 60% RH: 0.3 n/a (3.01) 90% RH:0.7 HCl n/a n/a MEK solvate Bis HCL 11.8 60% RH: 9.9 n/a (1.80) 90% RH:12.3 NDSA 0.3 n/a n/a (1.68) n/a—not analyzed CI—Counter-ion IC—IonChromatography

Example 22 Formulations and Dosage Forms Example 22A: CapsuleFormulations for Formula (I) Form C Polymorph

Capsules containing a compound of Formula (I) Form C polymorph (API)were prepared according to the following procedures. The capsulesincluded a hard gelatin capsule filled with a formulated dry blendpowder fill of Formula (I) Form C polymorph and one or more excipients.In some examples, the capsule components included Formula (I) Form Cpolymorph (about 1% to about 30% w/w); a filler/glidant such assilicified microcrystalline cellulose (about 70% to about 99% w/w); adisintegrant such as crospovidone (0% to about 7% w/w); and a lubricantsuch as magnesium stearate (0% to about 2% w/w).

Other excipients that can be used in exemplary capsule formulationsinclude, but are not limited to, fillers such as lactose, mannitol,starch, sorbitol, sucrose, dicalcium phosphate, and microcrystallinecellulose; disintegrants such as croscarmellose sodium and sodium starchglycolate; glidants such as colloidal silicon dioxide, silicon dioxide,magnesium silicate, and talc; lubricants such as sodium stearyl fumarateand stearic acid; and surfactants such as sodium lauryl sulphate, sodiumdodecyl sulphate, Tween® 80, and Lutrol®. The choice and the percentageof the filler/glidant can be based on the flowability of the blend. Thechoice and the parentage of the disintegrant can be based on the releaseprofile of the capsule in 0.1N Hydrochloric acid with no surfactants.

For a given formulation, part of the filler/glidant and the disintegrantwere each separately passed through a #30 mesh screen. The Formula (I)Form C polymorph and part of the filler/glidant were combined and passedthrough a #30 mesh screen. The lubricant was passed through a #40 meshscreen. Each component, except for the lubricant, was weighed andseparately transferred into a Patterson Kelley's V-blender and blendedfor about 5 to about 15 minutes after each addition. Then, the mixturewas milled through a Quadro® Comil® using a 0.039R mesh screen at about40 rpm speed. Finally, the lubricant was added and the mixture wasblended for about 5 minutes. The mixture was then used to fill theappropriate capsules using an IN-CAP encapsulation machine.

A non-limiting example of formulation and capsule preparation is givenin Table 14. A low strength formulation was prepared for the 1 mg/5 mgcapsules, and a high strength formulation was prepared for the 25 mg/100mg strengths. The 1 mg and 25 mg strengths were in size 2, opaque white,hard gelatin capsules while the 5 mg strength was in size 2, opaqueSwedish orange, hard gelatin capsules and the 100 mg strength was insize 0, opaque white, hard gelatin capsules.

TABLE 14 Capsule Formulations 1 mg and 25 mg and Components (% w/w) 5 mgcapsules 100 mg capsules Category Formula (I) Form C polymorph 2.3 25.0API Silicified Microcrystalline 91.7  68.5 Filler/Glidant Cellulose(SMCC), NF Crospovidone, EP, USP/NF, JP 5.0 5.0 Disintegrant MagnesiumStearate, NF, BP, JP 1.0 1.5 Lubricant Hard Gelatin Capsule 2 White (1mg) 2 White (25 mg)  Encapsulation 2 Swedish orange 0 White (100 mg) (5mg)

Example 22B: Large-scale Capsule Formulations for Formula (I) Form CPolymorph

The formulations were evaluated for their manufacturability, scalabilityto automated encapsulation equipment, content uniformity, dissolution,and stability. To evaluate the above mentioned factors, large scalebatches were manufactured for all strengths. For the 1/5 mg blend,approximately 2 kg of API formulation was manufactured as indicated inExample 22A, allowing production of about 9000 capsules of eachstrength. For the 25/100 mg blend, approximately 2.5 kg of APIformulation was manufactured as indicated in Example 22A, allowingproduction of about 6000 capsules of each strength. Tables 15 and 16below summarize the results of several assays of these formulations.

TABLE 15 1/5 mg Formulation Characteristics Assay 1 mg Capsules 5 mgCapsules Blend uniformity 2.4% w/w, 5% RSD before co-milling Blenduniformity 2.2% w/w, 4% RSD after co-milling Blend uniformity 2.3% w/w,4% RSD after lubrication Bulk and Tapped 0.58 0.68 Density (g/cc)Moisture Content 4.71 4.55 (% w/w) Assay of Capsules 102.0 98.0 (% LC)Purity (% a/a) 99.67 99.72 Content Uniformity 104.8 97.7 (% LC) AV, andRange 6.8, 102.4 - 106.6 6, 93.2 - 99.4 Dissolution 15 min - 88 15 min -83 (% LC) 30 min - 92 30 min - 91 45 min - 96 45 min - 94 60 min - 98 60min - 95 Inf. - 103 Inf. - 99

TABLE 16 25/100 mg Formulation Characteristics Assay 25 mg Capsules 100mg Capsules Blend uniformity 26.5% w/w, 2.2% RSD before lubricationBlend uniformity 24.7% w/w, 0.4% RSD after lubrication Bulk and Tapped0.40 0.61 Density (g/cc) Moisture Content 4.36 4.28 (% w/w) Assay ofCapsules 100.2 97.9 (% LC) Purity (% a/a) 99.6 99.6 Content Uniformity100.5 98.2 (% LC) AV, and Range 11, 94.7 - 107.7 7, 94.0 - 102.7Dissolution 15 min - 79 15 min - 86 (% LC) 30 min - 83 30 min - 87 45min - 84 45 min - 90 60 min - 86 60 min - 91 Inf. - 102 Inf. - 102

The stability of the capsules in a container closure was evaluated atlong-term and accelerated conditions. Container closure conditions usedwere (i) 60-cc high density polyethylene (HDPE), wide mouth, round,white bottle; and (ii) child resistant 33-mm white plastic cap with aheat induction foil inner seal liner. The containers containing thecapsules were subjected to the following conditions: (1) −20° C.±5° C.;(2) 5° C.±3° C.; (3) 25° C.±2° C., 60% RH±5% RH; (4) 40° C.±2° C., 75%RH±5% RH; (5) 25° C.±2° C., 60% RH±5% RH, open bottle; (6) 40° C.±2° C.,75% RH±5% RH, open bottle; and (7) 30° C.±2° C., 65% RH±5% RH. Samplesof the capsule formulations were analyzed at certain time intervals. TheAPI remained stable at 25° C.±2° C., 60% RH±5% RH and 40° C. 2° C.±45%RH±5% RH for at least 6 months. The API remained stable for at least 6month at −20° C.±5° C.±5° C.±3° C. when stored in induction-sealed HDPEbottles. The API was stable for at least 6 months at 25° C.±2° C., 60%RH±5% RH and 40° C.±2° C., 75% RH±5% RH in open HDPE bottles.

Manufacturing, packaging, labeling, storage, and testing of the capsuleswere performed in accordance with current Good Manufacturing Practices(cGMP). The capsules were packaged in High Density Polyethylene (HDPE)bottles. Other suitable packaging vessels include, but are not limitedto, glass bottles, low density polyethylene bottles/drums, fiber drums,HDPE drums, and blister packaging which can include materials likealuminum foil, Aclar®, and/or PVC/PVdC/PE films.

Karl Fischer analysis of the API in the capsules indicated a watercontent of between about 4% w/w and about 5% w/w (e.g., about 4.2%,about 4.3%, about 4.5%, about 4.7%, about 4.9%, about 5.0%)

A representative capsule dissolution profile for the 1, 5, 25, and 100mg capsules is shown in FIG. 31 . The dissolution of the capsules wasconsistent with that of an immediate-release solid oral dosage form. At60 min, greater than about 90% of API had been dissolved. Thedissolution conditions were USP Apparatus II (Paddle), 0.1 N HCl at 37°C., 500 mL (for 1, 5, 25 mg) or 900 mL (for 100 mg), 50 RPM paddlespeed.

Example 23 Biological Activity Assessment

A PI3-Kinase HTRF® assay kit (cat No. 33-016) purchased from MilliporeCorporation was used to screen compounds disclosed herein. This assayused specific, high affinity binding of the GRP1 pleckstrin homology(PH) domain to PIP3, the product of a Class IA or IB PI3 Kinase actingon its physiological substrate PIP2. During the detection phase of theassay, a complex was generated between the GST-tagged PH domain andbiotinylated short chain PIP3. The biotinylated PIP3 and the GST-taggedPH domain recruited fluorophores (Streptavidin-Allophycocyanin andEuropium-labeled anti-GST respectively) to form the fluorescenceresonance energy transfer (FRET) architecture, generating a stabletime-resolved FRET signal. The FRET complex was disrupted in acompetitive manner by non-biotinylated PIP3, a product formed in the PI3Kinase assay.

PI3 Kinase α, β, γ and δ activity was assayed using the PI3 Kinase HTRF®assay kit (catalogue No. 33-016) purchased from Millipore Corporation.Purified recombinant PI3Kα (catalogue No. 14-602-K), PI3Kβ (catalogueNo. 14-603-K), PI3Kγ (catalogue No. 14-558-K) and PI3Kδ (catalogue No.14-604-K) were obtained from Millipore Corporation. Purified recombinantPI3K enzyme was used to catalyze the phosphorylation ofphosphatidylinositol 4,5-bisphosphate (PIP2 at 10 μM) tophosphatidylinositol 3,4,5-trisphosphate (PIP3) in the presence of 10 μMATP. The assay was carried out in 384-well format and detected using aPerkin Elmer EnVision Xcite Multilabel Reader. Emission ratios wereconverted into percent inhibitions and imported into GraphPad Prism®software. The concentration necessary to achieve inhibition of enzymeactivity by 50% (IC₅₀) was calculated using concentrations ranging from20 μM to 0.1 nM (12-point curve). IC₅₀ values were determined using anonlinear regression model available in GraphPad Prism®5.

Example 24 Chemical Stability

The chemical stability of one or more subject compounds is determinedaccording to standard procedures known in the art. The following detailsan exemplary procedure for ascertaining chemical stability of a subjectcompound. The default buffer used for the chemical stability assay isphosphate-buffered saline (PBS) at pH 7.4; other suitable buffers can beused. A subject compound is added from a 100 μM stock solution to analiquot of PBS (in duplicate) to give a final assay volume of 400 μL,containing 5 μM test compound and 1% DMSO (for half-life determination atotal sample volume of 700 μL is prepared). Reactions are incubated,with shaking, for 24 hours at 37° C.; for half-life determinationsamples are incubated for 0, 2, 4, 6, and 24 hours. Reactions arestopped by adding immediately 100 μL of the incubation mixture to 100 μLof acetonitrile and vortexing for 5 minutes. The samples are then storedat −20° C. until analysis by HPLC-MS/MS. Optionally, a control compoundor a reference compound such as chlorambucil (5 μM) is testedsimultaneously with a subject compound of interest, as this compound islargely hydrolyzed over the course of 24 hours. Samples are analyzed via(RP)HPLC-MS/MS using selected reaction monitoring (SRM). The HPLCconditions consist of a binary LC pump with autosampler, a mixed-mode,C12, 2×20 mm column, and a gradient program. Peak areas corresponding tothe analytes are recorded by HPLC-MS/MS. The ratio of the parentcompound remaining after 24 hours relative to the amount remaining attime zero, expressed as percent, is reported as chemical stability. Incase of half-life determination, the half-life is estimated from theslope of the initial linear range of the logarithmic curve of compoundremaining (%) vs. time, assuming first order kinetics.

Example 25 Expression and Inhibition Assays of p110α/p85α, p110β/p85α,p110δ/p85α, and p110γ

Class 1 PI3-Ks can be either purchased (p110α/p85α, p110β/p85α,p110δ/p85α from Upstate, and p110γ from Sigma) or expressed aspreviously described (Knight et al., 2004). IC₅₀ values are measuredusing either a standard TLC assay for lipid kinase activity (describedbelow) or a high-throughput membrane capture assay. Kinase reactions areperformed by preparing a reaction mixture containing kinase, inhibitor(2% DMSO final concentration), buffer (25 mM HEPES, pH 7.4, 10 mMMgCl2), and freshly sonicated phosphatidylinositol (100 μg/ml).Reactions are initiated by the addition of ATP containing 10 μCi ofγ-32P-ATP to a final concentration of 10 or 100 μM and allowed toproceed for 5 minutes at room temperature. For TLC analysis, reactionsare then terminated by the addition of 105 μl 1N HCl followed by 160 μlCHCl₃:MeOH (1:1). The biphasic mixture is vortexed, briefly centrifuged,and the organic phase is transferred to a new tube using a gel loadingpipette tip precoated with CHCl₃. This extract is spotted on TLC platesand developed for 3-4 hours in a 65:35 solution of n-propanol:1M aceticacid. The TLC plates are then dried, exposed to a phosphorimager screen(Storm, Amersham), and quantitated. For each compound, kinase activityis measured at 10-12 inhibitor concentrations representing two-folddilutions from the highest concentration tested (typically, 200 μM). Forcompounds showing significant activity, IC₅₀ determinations are repeatedtwo to four times, and the reported value is the average of theseindependent measurements.

Other commercial kits or systems for assaying PI3-K activities areavailable. The commercially available kits or systems can be used toscreen for inhibitors and/or agonists of PI3-Ks including, but notlimited to, PI3-Kinase α, β, δ, and γ. An exemplary system is PI3-Kinase(human) HTRF® Assay from Upstate. The assay can be carried out accordingto the procedures suggested by the manufacturer. Briefly, the assay is atime resolved FRET assay that indirectly measures PIP3 product formed bythe activity of a PI3-K. The kinase reaction is performed in amicrotiter plate (e.g., a 384 well microtiter plate). The total reactionvolume is approximately 20 μl per well. In the first step, each wellreceives 2 μl of test compound in 20% dimethylsulphoxide resulting in a2% DMSO final concentration. Next, approximately 14.5 μl of akinase/PIP2 mixture (diluted in IX reaction buffer) is added per wellfor a final concentration of 0.25-0.3 μg/ml kinase and 10 μM PIP2. Theplate is sealed and incubated for 15 minutes at room temperature. Tostart the reaction, 3.5 μl of ATP (diluted in IX reaction buffer) isadded per well for a final concentration of 10 μM ATP. The plate issealed and incubated for 1 hour at room temperature. The reaction isstopped by adding 5 μl of Stop Solution per well and then 5 μl ofDetection Mix is added per well. The plate is sealed, incubated for 1hour at room temperature, and then read on an appropriate plate reader.Data is analyzed and IC₅₀s are generated using GraphPad Prism® 5.

Example 26 B Cell Activation and Proliferation Assay

The ability of one or more subject compounds to inhibit B cellactivation and proliferation is determined according to standardprocedures known in the art. For example, an in vitro cellularproliferation assay is established that measures the metabolic activityof live cells. The assay is performed in a 96 well microtiter plateusing alamarBlue® reduction. Balb/c splenic B cells are purified over aFicoll-Paque™ PLUS gradient followed by magnetic cell separation using aMACS B cell Isolation Kit (Miletenyi). Cells are plated in 90 μl at50,000 cells/well in B Cell Media (RPMI+10% FBS+Penn/Strcp+50 μM bME+5mM HEPES). A compound disclosed herein is diluted in B Cell Media andadded in a 10 μl volume. Plates are incubated for 72 hours at 37° C. and5% CO₂. A volume of 15 μL of alamarBlue® reagent is added to each welland plates am incubated for 5 hours at 37° C. and 5% CO₂. AlamarBlue®fluoresce is read at 560Ex/590Em, and IC₅₀ or EC₅₀ values are calculatedusing GraphPad Prism® 5.

Example 27 Tumor Cell Line Proliferation Assay

The ability of one or more subject compounds to inhibit tumor cell lineproliferation can be determined according to standard procedures knownin the art. For instance, an in vitro cellular proliferation assay canbe performed to measure the metabolic activity of live cells. The assayis performed in a 96 well microtiter plate using alamarBlue® reduction.Human tumor cell lines are obtained from ATCC (e.g., MCF7, U-87 MG,MDA-MB-468, PC-3), grown to confluency in T75 flasks, trypsinized with0.25% trypsin, washed one time with Tumor Cell Media (DMEM+10% FBS), andplated in 90 μl at 5,000 cells/well in Tumor Cell Media. A compounddisclosed herein is diluted in Tumor Cell Media and added in a 10 ulvolume. Plates are incubated for 72 hours at 37° C. and 5% CO₂. A volumeof 10 μL of alamarBlue® reagent is added to each well and plates amincubated for 3 hours at 37° C. and 5% CO₂. AlamarBlue® fluoresce isread at 560Ex/590Em, and IC₅₀ values are calculated using GraphPadPrism® 5.

Example 28 Antitumor Activity In Vivo

The compounds described herein can be evaluated in a panel of human andmurine tumor models.

Paclitaxel-refractory Tumor Models

1. Clinically-Derived Ovarian Carinoma Model.

This tumor model is established from a tumor biopsy of an ovarian cancerpatient. Tumor biopsy is taken from the patient. The compounds describedherein are administered to nude mice bearing staged tumors using anevery 2 days×5 schedule.

2. A278Tax Human Ovarian Carcinoma Xenograft (Mutated Tubulin).

A2780Tax is a paclitaxel-resistant human ovarian carcinoma model. It isderived from the sensitive parent A2780 line by co-incubation of cellswith paclitaxel and verapamil, an MDR-reversal agent. Its resistancemechanism has been shown to be non-MDR related and is attributed to amutation in the gene encoding the beta-tubulin protein. The compoundsdescribed herein can be administered to mice bearing staged tumors on anevery 2 days×5 schedule.

3. HCT116/VM46 Human Colon Carcinoma Xenograft (Multi-Drug Resistant).

HCT116/VM46 is an MDR-resistant colon carcinoma developed from thesensitive HCT116 parent line. In vivo, grown in nude mice, HCT116/VM46has consistently demonstrated high resistance to paclitaxel. Thecompounds described herein can be administered to mice bearing stagedtumors on an every 2 days×5 schedule.

4. M5076 Murine Sarcoma Model

M5076 is a mouse fibrosarcoma that is inherently refractory topaclitaxel in vivo. The compounds described herein can be administeredto mice bearing staged tumors on an every 2 days×5 schedule.

One or more compounds as disclosed herein can be used in combinationother therapeutic agents in vivo in the multidrug resistant human coloncarcinoma xenografts HCT/VM46 or any other model known in the artincluding those described herein.

Example 29 Microsome Stability Assay

The stability of one or more subject compounds is determined accordingto standard procedures known in the art. For example, stability of oneor mom subject compounds is established by an in vitro assay. Forexample, an in vitro microsome stability assay is established thatmeasures stability of one or more subject compounds when reacting withmouse, rat or human microsomes from liver. The microsome reaction withcompounds is performed in 1.5 mL Eppendorf tube. Each tube contains 0.1μL of 10.0 mg/ml NADPH; 75 μL of 20.0 mg/ml mouse, rat or human livermicrosome; 0.4 IL of 0.2 M phosphate buffer, and 425 μL of ddH₂O.Negative control (without NADPH) tube contains 75 μL of 20.0 mg/mlmouse, rat or human liver microsome; 0.4 μL of 0.2 M phosphate buffer,and 525 μL of ddH₂O. The reaction is started by adding 1.0 μL of 10.0 mMtested compound. The reaction tubes are incubated at 37° C. 100 μLsample is collected into new Eppendorf tube containing 300 μL coldmethanol at 0, 5, 10, 15, 30 and 60 minutes of reaction. Samples arecentrifuged at 15,000 rpm to remove protein. Supernatant of centrifugedsample is transferred to new tube. Concentration of stable compoundafter reaction with microsome in the supernatant is measured by LiquidChromatography/Mass Spectrometry (LC-MS).

Example 30 Plasma Stability Assay

The stability of one or more subject compounds in plasma is determinedaccording to standard procedures known in the art. See, e.g., RapidCommun. Mass Spectrom., 10: 1019-1026. The following procedure is anHPLC-MS/MS assay using human plasma; other species including monkey,dog, rat, and mouse are also available. Frozen, heparinized human plasmais thawed in a cold water bath and spun for 10 minutes at 2000 rpm at 4°C. prior to use. A subject compound is added from a 400 μM stocksolution to an aliquot of pre-warmed plasma to give a final assay volumeof 400 μL (or 800 μL for half-life determination), containing 5 μM testcompound and 0.5% DMSO. Reactions are incubated, with shaking, for 0minutes and 60 minutes at 37° C., or for 0, 15, 30, 45 and 60 minutes at37 C for half life determination. Reactions am stopped by transferring50 μL of the incubation mixture to 200 μL of ice-cold acetonitrile andmixed by shaking for 5 minutes. The samples are centrifuged at 6000×gfor 15 minutes at 4° C. and 120 μL of supernatant removed into cleantubes. The samples are then evaporated to dryness and submitted foranalysis by HPLC-MS/MS.

In one embodiment, one or more control or reference compounds (5 μM) aretested simultaneously with the test compounds: one compound,propoxycaine, with low plasma stability and another compound,propantheline, with intermediate plasma stability.

Samples are reconstituted in acetonitrile/methanol/water (1/I/2, v/v/v)and analyzed via (RP)HPLC-MS/MS using selected reaction monitoring(SRM). The HPLC conditions consist of a binary LC pump with autosampler,a mixed-mode, Cl2, 2×20 mm column, and a gradient program. Peak areascorresponding to the analytes are recorded by HPLC-MS/MS. The ratio ofthe parent compound remaining after 60 minutes relative to the amountremaining at time zero, expressed as percent, is reported as plasmastability. In case of half-life determination, the half-life isestimated from the slope of the initial linear range of the logarithmiccurve of compound remaining (%) vs. time, assuming first order kinetics.

Example 31 Kinase Signaling in Blood

PI3K/Akt/mTor signaling is measured in blood cells using the phosflowmethod (Methods Enzymol. (2007) 434:131-54). This method is by nature asingle cell assay so that cellular heterogeneity can be detected ratherthan population averages. This allows concurrent dinstinction ofsignaling states in different populations defined by other markers.Phosflow is also highly quantitative. To test the effects of one or morecompounds disclosed herein, unfractionated splenocytes, or peripheralblood mononuclear cells are stimulated with anti-CD3 to initiate T-cellreceptor signaling. The cells are then fixed and stained for surfacemarkers and intracellular phosphoproteins. Inhibitors disclosed hereininhibit anti-CD3 mediated phosphorylation of Akt-S473 and S6, whereasrapamycin inhibits S6 phosphorylation and enhances Akt phosphorylationunder the conditions tested.

Similarly, aliquots of whole blood am incubated for 15 minutes withvehicle (e.g., 0.1% DMSO) or kinase inhibitors at variousconcentrations, before addition of stimuli to crosslink the T cellreceptor (TCR) (anti-CD3 with secondary antibody) or the B cell receptor(BCR) using anti-kappa light chain antibody (Fah′2 fragments). Afterapproximately 5 and 15 minutes, samples are fixed (e.g., with cold 4%paraformaldehyde) and used for phosflow. Surface staining is used todistinguish T and B cells using antibodies directed to cell surfacemarkers that are known to the art. The level of phosphorylation ofkinase substrates such as Akt and S6 am then measured by incubating thefixed cells with labeled antibodies specific to the phosphorylatedisoforms of these proteins. The population of cells is then analyzed byflow cytometry.

Example 32 Colony Formation Assay

Murine bone marrow cells freshly transformed with a p190 BCR-Ablretrovirus (herein referred to as p190 transduced cells) are plated inthe presence of various drug combinations in M3630 methylcellulose mediafor about 7 days with recombinant human IL-7 in about 30% serum, and thenumber of colonies formed is counted by visual examination under amicroscope.

Alternatively, human peripheral blood mononuclear cells are obtainedfrom Philadelphia chromosome positive (Ph+) and negative (Ph−) patientsupon initial diagnosis or relapse. Live cells am isolated and enrichedfor CDI9+ CD34+ B cell progenitors. After overnight liquid culture,cells are plated in methocult GF+ H4435, Stem Cell Technologies)supplemented with cytokines (IL-3, IL-6, IL-7, G-CSF, GM-CSF, CF, Flt3ligand, and erythropoietin) and various concentrations of knownchemotherapeutic agents in combination with either compounds of thepresent disclosure. Colonies am counted by microscopy 12-14 days later.This method can be used to test for evidence of additive or synergisticactivity.

Example 33 In Vivo Effect of Kinase Inhibitors on Leukemic Cells

Female recipient mice are lethally irradiated from a γ source in twodoses about 4 hr apart, with approximately 5 Gy each. About 1 hr afterthe second radiation dose, mice are injected i.v. with about 1×10⁶leukemic cells (e.g., Ph+ human or murine cells, or p190 transduced bonemarrow cells). These cells ae administered together with aradioprotective dose of about 5×10⁶ normal bone marrow cells from 3-5week old donor mice. Recipients are given antibiotics in the water andmonitored daily. Mice who become sick after about 14 days am euthanizedand lymphoid organs are harvested for analysis. Kinase inhibitortreatment begins about 10 days after leukemic cell injection andcontinues daily until the mice become sick or a maximum of approximately35 days post-transplant. Inhibitors arm given by oral lavage.

Peripheral blood cells are collected approximately on day 10(pre-treatment) and upon euthanization (post treatment), contacted withlabeled anti-hCD4 antibodies and counted by flow cytometry. This methodcan be used to demonstrate that the synergistic effect of one or morecompounds disclosed herein in combination with known chemotherapeuticagents can reduce leukemic blood cell counts as compared to treatmentwith known chemotherapeutic agents (e.g., Gleevec®) alone under theconditions tested.

Example 34 Treatment of Lupus Disease Model Mice

Mice lacking the inhibitory receptor FcγRIIb that opposes PI3K signalingin B cells develop lupus with high penetrance. FcγRIIb knockout mice(R2KO, Jackson Labs) are considered a valid model of the human diseaseas some lupus patients show decreased expression or function of FcγRIIb(S. Bolland and J. V. Ravtech 2000. Immunity 12:277-285).

The R2KO mice develop lupus-like disease with anti-nuclear antibodies,glomerulonephritis and proteinurea within about 4-6 months of age. Forthese experiments, the rapamycin analogue RAD001 (available from LCLaboratories) is used as a benchmark compound, and administered orally.This compound has been shown to ameliorate lupus symptoms in theB6.Sle1z.Sle3z model (T. Wu et al. J. Clin Invest. 117:2186-2196).

Lupus disease model mice such as R2KO. BXSB or MLR/Ipr are treated atabout 2 months old, approximately for about two months. Mice are givendoses of: vehicle, RAD001 at about 10 mg/kg, or compounds disclosedherein at approximately 1 mg/kg to about 500 mg/kg. Blood and urinesamples are obtained at approximately throughout the testing period, andtested for antinuclear antibodies (in dilutions of serum) or proteinconcentration (in urine). Serum is also tested for anti-ssDNA andanti-dsDNA antibodies by ELISA. Animals are euthanized at day 60 andtissues harvested for measuring spleen weight and kidney disease.Glomerulonephritis is assessed in kidney sections stained with H&E.Other animals are studied for about two months after cessation oftreatment, using the same endpoints.

This established art model can be employed to demonstrate that thekinase inhibitors disclosed herein can suppress or delay the onset oflupus symptoms in lupus disease model mice.

Example 35 Murine Bone Marrow Transplant Assay

Female recipient mice are lethally irradiated from ay ray source. About1 hr after the radiation dose, mice are injected with about 1×106leukemic cells from early passage p190 transduced cultures (e.g., asdescribed in Cancer Genet Cytogenet. 2005 August; 161(1):51-6). Thesecells are administered together with a radioprotective dose ofapproximately 5×10⁶ normal bone marrow cells from 3-5 wk old donor mice.Recipients are given antibiotics in the water and monitored daily. Micewho become sick after about 14 days are euthanized and lymphoid organsharvested for flow cytometry and/or magnetic enrichment. Treatmentbegins on approximately day 10 and continues daily until mice becomesick, or after a maximum of about 35 days post-transplant. Drugs aregiven by oral gavage (p.o.). In a pilot experiment a dose ofchemotherapeutic that is not curative but delays leukemia onset by aboutone week or less is identified; controls are vehicle-treated or treatedwith chemotherapeutic agent, previously shown to delay but not cureleukemogenesis in this model (e.g., imatinib at about 70 mg/kg twicedaily). For the first phase p190 cells that express eGFP are used, andpostmortem analysis is limited to enumeration of the percentage ofleukemic cells in bone marrow, spleen and lymph node (LN) by flowcytometry. In the second phase, p190 cells that express a tailless formof human CD4 are used and the postmortem analysis includes magneticsorting of hCD4+ cells from spleen followed by immunoblot analysis ofkey signaling endpoints: p Akt-T308 and S473; pS6 and p4EBP-1. Ascontrols for immunoblot detection, sorted cells are incubated in thepresence or absence of kinase inhibitors of the present disclosureinhibitors before lysis. Optionally, “phosflow” is used to detect pAkt-S473 and pS6-S235/236 in hCD4-gated cells without prior sorting.These signaling studies are particularly useful if, for example,drug-treated mice have not developed clinical leukemia at the 35 daytime point. Kaplan-Meier plots of survival are generated and statisticalanalysis done according to methods known in the art. Results from p190cells are analyzed separated as well as cumulatively.

Samples of peripheral blood (100-200 μl) arm obtained weekly from allmice, starting on day 10 immediately prior to commencing treatment.Plasma is used for measuring drug concentrations, and cells are analyzedfor leukemia markers (eGFP or hCD4) and signaling biomarkers asdescribed herein.

This general assay known in the art can be used to demonstrate thateffective therapeutic doses of the compounds disclosed hemin can be usedfor inhibiting the proliferation of leukemic cells.

Example 36 Matrigel Plug Angiogenesis Assay

Matrigel containing test compounds arm injected subcutaneously orintraocularly, where it solidifies to form a plug. The plug is recoveredafter 7-21 days in the animal and examined histologically to determinethe extent to which blood vessels have entered it. Angiogenesis ismeasured by quantification of the vessels in histologic sections.Alternatively, fluorescence measurement of plasma volume is performedusing fluorescein isothiocyanate (FITC)-labeled dextran 150. The resultsare expected to indicate one or more compounds disclosed herein thatinhibit angiogenesis and are thus expected to be useful in treatingocular disorders related to aberrant angiogenesis and/or vascularpermeability.

Example 37 Corneal Angiogenesis Assay

A pocket is made in the cornea, and a plug containing an angiogenesisinducing formulation (e.g., VEGF, FGF, or tumor cells), when introducedinto this pocket, elicits the ingrowth of new vessels from theperipheral limbal vasculature. Slow-release materials such as Elvax®(ethylene vinyl copolymer) or Hydron are used to introduce angiogenesisinducing substances into the corneal pocket. Alternatively, a spongematerial is used.

The effect of putative inhibitors on the locally induced (e.g., spongeimplant) angiogenic reaction in the cornea (e.g., by FGF, VEGF, or tumorcells). The test compound is administered orally, systemically, ordirectly to the eye. Systemic administration is by bolus injection or,more effectively, by use of a sustained-release method such asimplantation of osmotic pumps loaded with the test inhibitor.Administration to the eye is by any of the methods described hereinincluding, but not limited to eye drops, topical administration of acream, emulsion, or gel, intravitreal injection.

The vascular response is monitored by direct observation throughout thecourse of the experiment using a stereomicroscope in mice. Definitivevisualization of the corneal vasculature is achieved by administrationof fluorochrome-labeled high-molecular weight dextran. Quantification isperformed by measuring the area of vessel penetration, the progress ofvessels toward the angiogenic stimulus over time, or in the case offluorescence, histogram analysis or pixel counts above a specific(background) threshold.

The results can indicate one or more compounds disclosed herein inhibitangiogenesis and thus can be useful in treating ocular disorders relatedto aberrant angiogenesis and/or vascular permeability.

Example 38 Microtiter-Plate Angiogenesis Assay

The assay plate is prepared by placing a collagen plug in the bottom ofeach well with 5-10 cell spheroids per collagen plug each spheroidcontaining 400-500 cells. Each collagen plug is covered with 1100 μl ofstorage medium per well and stored for future use (1-3 days at 37° C.,5% CO₂). The plate is sealed with sealing. Test compounds are dissolvedin 200 μl assay medium with at least one well including a VEGF positivecontrol and at least one well without VEGF or test compound as anegative control, the assay plate is removed from the incubator andstorage medium is carefully pipeted away. Assay medium containing thetest compounds are pipeted onto the collagen plug. The plug is placed ina humidified incubator for (37° C., 5% CO₂) 24-48 hours. Angiogenesis isquantified by counting the number of sprouts, measuring average sproutlength, or determining cumulative sprout length, the assay can bepreserved for later analysis by removing the assay medium, adding 1 mlof 10% paraformaldehyde in Hanks BSS per well, and storing at 4° C. Theresults are expected to identify compounds that inhibit angiogenesis invarious cell types tested, including cells of ocular origin.

Example 39 Combination Use of PI3K-δ Inhibitors and Agents that InhibitIgE Production or Activity

The compounds as disclosed herein can present synergistic or additiveefficacy when administered in combination with agents that inhibit IgEproduction or activity. Agents that inhibit IgE production include, forexample, one or more of TEI-9874,2-(4-(6-cyclohexyloxy-2-naphtyloxy)phenylacetamide)benzoic acid,rapamycin, rapamycin analogs (i.e., rapalogs), TORC1 inhibitors, TORC2inhibitors, and any other compounds that inhibit mTORC1 and mTORC2.Agents that inhibit IgE activity include, for example, anti-IgEantibodies such as Omalizumab and TNX-901.

One or more of the subject compounds capable of inhibiting PI3K-δ can beefficacious in treatment of autoimmune and inflammatory disorders(AIID), for example, rheumatoid arthritis. If any of the compoundscauses an undesired level of IgE production, one can choose toadminister it in combination with an agent that inhibits IgE productionor IgE activity. Additionally, the administration of PI3K-δ or PI3K-δ/γinhibitors as disclosed herein in combination with inhibitors of mTORcan also exhibit synergy through enhanced inhibition of the PI3Kpathway. Various in vivo and in vitro models can be used to establishthe effect of such combination treatment on AIID including, but notlimited to (a) in vitro B-cell antibody production assay, (b) in vivoTNP assay, and (c) rodent collagen induced arthritis model.

(a) B-Cell Assay

Mice are euthanized, and the spleens are removed and dispersed through anylon mesh to generate a single-cell suspension. The splenocytes arewashed (following removal of erythrocytes by osmotic shock) andincubated with anti-CD43 and anti-Mac-1 antibody-conjugated microbeads(Miltenyi Biotec). The bead-bound cells are separated from unbound cellsusing a magnetic cell sorter. The magnetized column retains the unwantedcells and the resting B cells are collected in the flow-through.Purified B-cells are stimulated with lipopolysaccharide or an anti-CD40antibody and interleukin 4. Stimulated B-cells are treated with vehiclealone or with PI3K-δ inhibitors as disclosed herein with and withoutmTOR inhibitors such as rapamycin, rapalogs, or mTORC1/C2 inhibitors.The results are expected to show that in the presence of mTOR inhibitors(e.g., rapamycin) alone, there is little to no substantial effect on IgGand IgE response. However, in the presence of PI3K-δ and mTORinhibitors, the B-cells are expected to exhibit a decreased IgG responseas compared to the B-cells treated with vehicle alone, and the B-cellsare expected to exhibit a decreased IgE response as compared to theresponse from B-cells treated with PI3K-δ inhibitors alone.

(b) TNP Assay

Mice are immunized with TNP-Ficoll or TNP-KHL and treated with: vehicle,a PI3K-δ inhibitor, an mTOR inhibitor, for example rapamycin, or aPI3K-δ inhibitor in combination with an mTOR inhibitor such asrapamycin. Antigen-specific serum IgE is measured by ELISA using TNP-BSAcoated plates and isotype specific labeled antibodies. It is expectedthat mice treated with an mTOR inhibitor alone exhibit little or nosubstantial effect on antigen specific IgG3 response and nostatistically significant elevation in IgE response as compared to thevehicle control. It is also expected that mice treated with both PI3K-δinhibitor and mTOR inhibitor exhibit a reduction in antigen specificIgG3 response as compared to the mice treated with vehicle alone.Additionally, the mice treated with both PI3K-δ inhibitor and mTORinhibitor exhibit a decrease in IgE response as compared to the micetreated with PI3K-δ inhibitor alone.

(c) Rat Collagen Induced Arthritis Model

Female Lewis rats are anesthetized and given collagen injectionsprepared and administered as described previously on day 0. On day 6,animals am anesthetized and given a second collagen injection. Calipermeasurements of normal (pre-disease) right and left ankle joints areperformed on day 9. On days 10-11, arthritis typically occurs and ratsare randomized into treatment groups. Randomization is performed afterankle joint swelling is obviously established and there is good evidenceof bilateral disease.

After an animal is selected for enrollment in the study, treatment isinitiated. Animals are given vehicle, PI3K-δ inhibitor, or PI3K-δinhibitor in combination with rapamycin. Dosing is administered on days1-6. Rats are weighed on days 1-7 following establishment of arthritisand caliper measurements of ankles taken every day. Final body weightsare taken on day 7 and animals are euthanized.

The combination treatment using a compound as disclosed herein andrapamycin can provide greater efficacy than treatment with PI3K-δinhibitor alone.

Example 40 Delayed Type Hypersensitivity Model

DTH was induced by sensitizing 60 BALB/c male mice on day 0 and day 1with a solution of 0.05% 2,4 dinitrofluorobenzene (DNFB) in a 4:1acetone/olive oil mixture. Mice were gently restrained while 20 μL ofsolution was applied to the hind foot pads of each mouse. The hind footpads of the mice were used as they represent an anatomical site that canbe easily isolated and immobilized without anesthesia. On day 5, micewere administered a single dose of vehicle, a compound disclosed hereinat 10, 3, 1, or 0.3 mg/kg, or dexamethasone at a dose of 5 mg/kg by oralgavage. Thirty minutes later mice were anaesthetized, and a solution of0.25% DNFB in a 4:1 acetone/olive oil solution was applied to the leftinner and outer ear surface. This application resulted in the inductionof swelling to the left ear and under these conditions, all animalsresponded to this treatment with car swelling. A vehicle controlsolution of 4:1 acetone/olive oil was applied to the right inner andouter ear. Twenty four hours later, mice were anaesthetized, andmeasurements of the left and right ear were taken using a digitalmicrometer. The difference between the two car was recorded as theamount of swelling induced by the challenge of DNFB. Drug treatmentgroups were compared to vehicle control to generate the percentreduction in ear swelling. Dexamethasone is routinely used as a positivecontrol as it has broad anti-inflammatory activity.

Example 41 Peptidoglycan-Polysaccharide Rat Arthritic Model

(a) Systemic Arthritis Model

All injections are performed under anesthesia. 60 female Lewis rats(150-170) are anesthetized by inhalation isoflurane using a small animalanesthesia machine. The animals are placed in the induction chamberuntil anesthetized by delivery of 4-5% isoflurane in O₂ and then held inthat state using a nose cone on the procedure table. Maintenance levelof isoflurane is at 1-2%. Animals am injected intraperitoneally (i.p.)with a single injection of purified PG-PS 10S Group A, D59 strain(concentration 25 μg/g of bodyweight) suspended in sterile 0.85% saline.Each animal receives a total volume of 500 microliters administered inthe lower left quadrant of the abdomen using a 1 milliliter syringe witha 23 gauge needle. Placement of the needle is critical to avoidinjecting the PG-PS 10S into cither the stomach or caccum. Animals areunder continuous observation until fully recovered from anesthesia andmoving about the cage. An acute response of a sharp increase in anklemeasurement, typically 20% above baseline measurement can peak in 3-5days post injection. Treatment with test compounds can be PO, SC, IV orIP. Rats are dosed no more than two times in a 24 hour time span.Treatment can begin on day 0 or any day after that through day 30. Theanimals are weighed on days 0, 1, 2, 3, 4, 5, 6, 7 and beginning againon day 12-30 or until the study is terminated. Paw/ankle diameter ismeasured with a digital caliper on the left and right side on day 0prior to injection and again on day 1, 2, 3, 4, 5, 6 and 7. On day 12,measurements begin again and continue on through day 30. At this time,animals can be anesthetized with isoflurane, as described above, andterminal blood samples can be obtained by tail vein draws for theevaluation of the compound blood levels, clinical chemistry orhematology parameters. Animals are them euthanized with carbon dioxideoverdose. A thoracotomy can be conducted as a means of deathverification.

(b) Monoarticular Arthritis Model

All injections are performed under anesthesia. 60 female Lewis rats(150-170) are anesthetized by inhalation isoflurane using a small animalanesthesia machine. The animals are placed in the induction chamberuntil anesthetized by delivery of 4-5% isoflurane in O₂ and then held inthat state using a nose cone on the procedure table. Maintenance levelof isoflurane is at 1-2%. Animals are injected intra-articular (i.a.)with a single injection of purified PG-PS 100P Group A, D58 strain(concentration 500 ug/ML) suspended in sterile 0.85% saline. Each ratreceives a total volume of 10 microliters administered into thetibiotalar joint space using a 1 milliliter syringe with a 27 gaugeneedle. Animals are under continuous observation until fully recoveredfrom anesthesia and moving about the cage. Animals that respond 2-3 dayslater with a sharp increase in ankle measurement, typically 20% abovebaseline measurement on the initial i.a, injection, are included in thestudy. On day 14, all responders are anesthetized again using theprocedure previously described. Animals receive an intravenous (I.V.)injection of PG-PS (concentration 250 uL/mL). Each rat receives a totalvolume of 400 microliters administered slowly into the lateral tail veinusing a 1 milliliter syringe with a 27 gauge needle. Baseline anklemeasurements are measured prior to IV injection and continue through thecourse of inflammation or out to day 10. Treatment with test compoundswill be PO, SC, IV or IP. Rats are dosed no more than two times in a 24hour time span. Treatment can begin on day 0 or any day after thatthrough day 24. The animals are weighed on days 0, 1, 2, 3, 4, 5, andbeginning again on day 14-24 or until the study is terminated. Paw/anklediameter is measured with a digital caliper on the left and right sideon day 0 prior to injection and again on day 1, 2, 3, 4, 5, andbeginning again on day 14-24 or until the study is terminated. At thistime, animals can be anesthetized with isoflurane, as described above,and terminal blood samples can be obtained by tail vein draws for theevaluation of the compound blood levels, clinical chemistry orhematology parameters. Animals are them euthanized with carbon dioxideoverdose. A thoracotomy can be conducted as a means of deathverification.

Example 42 Pharmacokinetic Data for Single and Repeat Dosing

A randomized, double-blind, placebo-controlled, single and repeat dosestudy was conducted to evaluate the pharmacokinetics (PK) of a compoundof Formula (I) Form C polymorph when orally administered to healthyadult male and female subjects. Subjects received a single oral dose ofa compound of Formula (I) Form C polymorph under fasting conditions at adose of 1 mg, 2 mg, 5 mg, 10 mg, 20 mg, and 30 mg. Blood samples werecollected for plasma analysis pre-dose, and at 0.5, 1, 1.5, 2, 3, 4, 6,9, 12, 16, and 24 hours. Doses of 1 mg, 2 mg, 5 mg, 10 mg, 20 mg, and 30mg gave a C_(max) value range of greater than 10 ng/nL to less than1,500 ng/mL, an AUC₀₋₂₄ value range of greater than 100 ng*h/mL to lessthan 4,000 ng*h/mL, and a half-life value range of greater than 3 hoursto less than 10 hours, in a dose dependent manner.

Repeat oral dose administration of a compound of Formula (I) Form Cpolymorph was administered once per day (QD) in the morning on Days 1and 14 and twice daily (BID) on Days 2 through 13. Administration of thecompound occurred after an overnight fast on Days 1 and 14. Bloodsamples were collected for plasma analysis on Day 14 following 1, 2, 5and 10 mg repeat dosing. Blood samples were collected on Day 14 prior todosing and at 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 16 and 24 hours afteradministration to determine plasma concentrations of the compound ofFormula (I) Form C polymorph. Doses of 1 mg, 2 mg, 5 mg, and 10 mg gavea C_(max) value range of greater than 10 ng/mL to less than 1,000 ng/mLin a dose dependent manner. In addition doses of 1 mg, 2 mg, 5 mg, and10 mg gave an AUC_(tau,ss) value range of greater than 100 ng*h/mL toless than 2,500 ng*h/mL, in a dose dependent manner. For the BIDregimens, the AUC over a 24 hour interval was obtained by multiplyingAUC_(tau,ss) by 2.

While various embodiments of the present disclosure have been shown anddescribed herein, it will be apparent to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the present disclosure. It should beunderstood that various alternatives to the embodiments of thedisclosure described herein can be employed in view of the presentdisclosure.

1. A compound of Formula (I):

Formula (I), wherein the compound is polymorph Form B, Form C, Form D,Form E, Form F, Form G, Form H, Form I, Form J, or an amorphous form ofa compound of Formula (I), or a salt, solvate, or hydrate thereof; or amixture of two or more thereof.
 2. A mixture of two or more compounds ofFormula (I):

wherein the compounds of Formula (I) are selected from: i) polymorphForm C, or a salt, solvate, or hydrate thereof; and ii) at least onenon-Form C polymorph selected from Form A, Form B, Form D, Form E, FormF, Form G, Form H, Form I, Form J, or an amorphous form of a compound ofFormula (I), or a salt, solvate, or hydrate thereof.
 3. A mixture of twoor more compounds of Formula (I):

wherein the compounds of Formula (I) are selected from: i) polymorphForm A, or a salt, solvate, or hydrate thereof; and ii) at least onenon-Form A polymorph selected from Form B, Form C, Form D, Form E, FormF, Form G, Form H, Form I, Form J, or an amorphous form of a compound ofFormula (I), or a salt, solvate, or hydrate thereof.
 4. A mixtureaccording to claim 2, wherein the mixture is at least 50% by weightpolymorph Form C, or a salt, solvate, or hydrate thereof.
 5. Thecompound of claim 1, which is Polymorph Form C of a compound of Formula(I):


6. The polymorph according to claim 5, wherein the polymorph has thefollowing characteristic X-ray Powder Diffraction (XRPD) peaks: 20=10.4°(±0.2°), 13.3° (±0.2°), and 24.3° (±0.2°).
 7. The polymorph according toclaim 6, further comprising at least one characteristic XRPD peakselected from 20=6.6° (±0.2°) and 12.5° (±0.2°).
 8. The polymorphaccording to claim 5, wherein the polymorph has the followingcharacteristic XRPD peaks: 20=6.6° (±0.2°), 10.4° (±0.2°), 12.5°(±0.2°), 13.3° (±0.2°), and 24.3° (±0.2°), in combination with at leastone XRPD peak selected from 20=8.8° (±0.2°), 9.9° (±0.2°), 13.4°(±0.2°), 15.50 (±0.2°), 16.9° (±0.2°), 19.8° (±0.2°), 21.3° (±0.2°),23.6° (±0.2°), 25.3° (±0.2°), and 27.9° (±0.2°).
 9. The polymorphaccording to claim 5, wherein the polymorph has substantially all peaksin its XRPD pattern as shown in FIG. 3 .
 10. The compound of claim 1,which is Polymorph Form B of a compound of Formula (I):


11. The polymorph according to claim 10, wherein the polymorph has thefollowing characteristic XRPD peaks: 20=7.9° (±0.2°), 13.4° (±0.2°), and23.4° (±0.2°).
 12. The polymorph according to claim 11, furthercomprising at least one characteristic XRPD peak selected from 20=14.0°(±0.2°) and 15.0° (±0.2°).
 13. The polymorph according to claim 10,wherein the polymorph has the following characteristic XRPD peaks:20=7.9° (±0.2°), 13.4° (±0.2°), 14.0° (±0.2°), 15.0° (±0.2°), and 23.4°(±0.2°), in combination with at least one XRPD peak selected from20=9.5° (±0.2°), 12.7° (±0.2°), 13.6° (±0.2°), 14.2° (±0.2°), 15.7°(±0.2°), 19.0° (±0.2°), 22.3° (±0.2°), 24.2° (±0.2°), 24.8° (±0.2°), and26.9° (±0.2°).
 14. The polymorph according to claim 10, wherein thepolymorph has substantially all peaks in its XRPD pattern as shown inFIG. 2 .
 15. The compound of claim 1, which is Polymorph Form D of acompound of Formula (I):


16. The polymorph according to claim 15, wherein the polymorph has thefollowing characteristic XRPD peaks: 20=11.4° (±0.2°), 17.4° (±0.2°),and 22.9° (±0.2°).
 17. The polymorph according to claim 16, furthercomprising at least one characteristic XRPD peak selected from 20=9.2°(±0.2°) and 18.3° (±0.2°).
 18. The polymorph according to claim 15,wherein the polymorph has the following characteristic XRPD peaks:20=9.2° (±0.2°), 11.4° (±0.2°), 17.4° (±0.2°), 18.3° (±0.2°), and 22.9°(±0.2°), in combination with at least one XRPD peak selected from20=9.8° (±0.20), 12.2° (±0.2°), 15.8° (±0.2°), 16.2° (±0.2°), 16.8°(±0.2°), 18.9° (±0.2°), 19.9° (±0.2°), 20.0° (±0.2°), 24.9° (±0.2°), and29.3° (±0.2°).
 19. The polymorph according to claim 15, wherein thepolymorph has substantially all peaks in its XRPD pattern as shown inFIG. 4 .
 20. The compound of claim 1, which is Polymorph Form E of acompound of Formula (I):

21-68. (canceled)